Oestrogen replacement therapy and coronary heart disease

This review highlights recent progress in our understanding of the beneficial effects of hormone replacement therapy (HRT) in cardiovascular disease (CVD). The fact that HRT is increasingly advocated has raised concern about possible adverse effects weighed against the potential benefits of HRT regimens. Both favourable and unfavourable effects of oestrogens and HRT regimens on CVD risk factors are increasingly recognized. Consequently, the picture on cardiovascular effects of oestrogen and HRT has become more complicated, and research in this field has extended to novel areas.     

Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease

Epidemiological and experimental studies suggest vascular protective effects of estrogen. Cardiovascular disease (CVD) is less common in premenopausal women than in men and postmenopausal women. Cytosolic/nuclear estrogen receptors (ERs) have been shown to mediate genomic effects that stimulate endothelial cell growth but inhibit vascular smooth muscle proliferation. However, the Heart and Estrogen/Progestin Replacement Study (HERS), HERS-II and Women’s Health Initiative clinical trials demonstrated that hormone replacement therapy (HRT) may not provide vascular benefits in postmenopausal women and may instead trigger adverse cardiovascular events. HRT may not provide vascular benefits because of the type of hormone used. Oral estrogens are biologically transformed by first-pass metabolism in the liver. By contrast, transdermal preparations avoid first pass metabolism. Also, natural estrogens and phytoestrogens may provide alternatives to synthetic estrogens. Furthermore, specific ER modulators could minimize the adverse effects of HRT, including breast cancer. HRT failure in CVD could also be related to changes in vascular ERs. Genetic polymorphism and postmenopausal decrease in vascular ERs or the downstream signaling mechanisms may reduce the effects of HRT. HRT in the late postmenopausal period may not be as effective as during menopausal transition. Additionally, while HRT may aggravate pre-existing CVD, it may thwart its development if used in a timely fashion. Lastly, the vascular effects of progesterone and testosterone, as well as modulators of their receptors, may modify the effects of estrogen and thereby provide alternative HRT strategies. Thus, the beneficial effects of HRT in postmenopausal CVD can be enhanced by customizing the HRT type, dose, route of administration and timing depending on the subject’s age and cardiovascular condition.     

Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease

Epidemiological and experimental studies suggest vascular protective effects of estrogen. Cardiovascular disease (CVD) is less common in premenopausal women than in men and postmenopausal women. Cytosolic/nuclear estrogen receptors (ERs) have been shown to mediate genomic effects that stimulate endothelial cell growth but inhibit vascular smooth muscle proliferation. However, the Heart and Estrogen/Progestin Replacement Study (HERS), HERS-II and Women's Health Initiative clinical trials demonstrated that hormone replacement therapy (HRT) may not provide vascular benefits in postmenopausal women and may instead trigger adverse cardiovascular events. HRT may not provide vascular benefits because of the type of hormone used. Oral estrogens are biologically transformed by first-pass metabolism in the liver. By contrast, transdermal preparations avoid first pass metabolism. Also, natural estrogens and phytoestrogens may provide alternatives to synthetic estrogens. Furthermore, specific ER modulators could minimize the adverse effects of HRT, including breast cancer. HRT failure in CVD could also be related to changes in vascular ERs. Genetic polymorphism and postmenopausal decrease in vascular ERs or the downstream signaling mechanisms may reduce the effects of HRT. HRT in the late postmenopausal period may not be as effective as during menopausal transition. Additionally, while HRT may aggravate pre-existing CVD, it may thwart its development if used in a timely fashion. Lastly, the vascular effects of progesterone and testosterone, as well as modulators of their receptors, may modify the effects of estrogen and thereby provide alternative HRT strategies. Thus, the beneficial effects of HRT in postmenopausal CVD can be enhanced by customizing the HRT type, dose, route of administration and timing depending on the subject's age and cardiovascular condition.     

Treating hot flashes in breast cancer survivors: a review of alternative treatments to hormone replacement therapy

As the number of breast cancer survivors continues to grow, factors associated with quality of life are receiving increased clinical and research attention. This attention is imperative given the aftermath of psychological and physiologic side effects that commonly result from a cancer diagnosis and cancer-related treatments, including menopausal symptoms. Hot flashes, the most prevalent of these symptoms, have been shown to significantly decrease quality of life in women. Although manageable with hormone replacement therapy (HRT), hot flashes often are especially problematic in breast cancer survivors, a population that typically is not treated with HRT because of controversial evidence of a relationship among estrogen and/or progesterone and breast cancer recurrence and mortality. Furthermore, hot flashes commonly are more severe in premenopausal women who experience acute menopause as a result of chemotherapy treatment. In recent years, several treatment alternatives to HRT have been investigated. Given the significant number of women affected by breast cancer and the negative impact that hot flashes can have on their quality of life, this article reviews alternatives to HRT for reducing hot flash symptoms in breast cancer survivors.     

Changes in muscle strength in women following the menopause: a longitudinal assessment of the efficacy of hormone replacement therapy.

The effects of hormone deficiency at the menopause on muscle strength was examined in 10 healthy middle-aged women (1-3 years post-menopause) in a longitudinal trial over 39 weeks. Performance was compared with that of age-matched females (n=11) taking a course of hormone replacement therapy (HRT). Muscle strength of the quadriceps was measured isometrically at 90 degrees of knee flexion and at angular velocities of 1.05, 2.09 and 3.13 rad/s using an isokinetic dynamometer. Hand grip strength was assessed by means of a portable dynamometer. Measurements were taken every 13 weeks for 39 weeks. Significant decreases in isometric strength (-10%) and dynamic leg strength at 1.05 rad/s (-9%) were found in the post-menopausal women over 39 weeks. There was no change in strength in the HRT group. There were also no changes in leg strength at higher angular velocities or in grip strength for either the post-menopausal group or those taking HRT. While HRT preserved muscle strength, there was no evidence of a strengthening effect on skeletal muscle within this short period of treatment. A rapid loss of leg strength occurs post-menopausally in hormone-depleted women. HRT may offer protection against muscle weakness, although the hormone responsible for regulating strength is not evident using this model.     

The case for hormone replacement: new studies that should inform the debate

The Women's Health Initiative found that the risks of hormone replacement therapy (HRT) exceeded its benefits in a large group of older postmenopausal women, but did not consider the efficacy of HRT in relieving vasomotor symptoms. Another recent study found that low-dose HRT was as effective as standard-dose HRT while causing fewer side effects. Smaller studies suggest that HRT may improve depression. HRT is not to be used for cardiovascular risk reduction. Genetic testing may point the way to more rational use of HRT.     

Effects of postmenopausal hormone replacement therapy on HbA(1c) levels

OBJECTIVE: Estrogen seems to contribute to glucose homeostasis in women. The objective of this study was to examine the effects of hormone replacement therapy (HRT) on HbA(1c) levels in Japanese postmenopausal women and to determine whether the effects varied with age. RESEARCH DESIGN AND METHODS: We studied 99 postmenopausal women taking HRT (mean +/- SD age 56.5 +/- 6.9 years, BMI 21.5 +/- 2.3 kg/m(2)) and 101 postmenopausal women not on HRT (51.4 +/- 6.1 years, 21.3 +/- 2.4 kg/m(2)). HRT consisted of continuous conjugated equine estrogen (CEE; 0.625 mg/day) and medroxyprogesterone acetate (MPA; 2.5 mg/day) for >2 years. RESULTS: HbA(1c) levels are positively associated with age and BMI in women who use HRT as well as in those who do not use HRT. After adjusting for age and BMI, HRT showed no effects on HbA(1c) levels. However, HbA(1c) levels were significantly lower in postmenopausal women aged 40-49 years who were taking HRT than in women of similar age who were not taking HRT (mean +/- SE 4.776 +/- 0.092 vs. 5.096 +/- 0.078%, P < 0.05). No differences in HbA(1c) levels between women who did and did not use HRT were observed in those older than 50 years. CONCLUSIONS: Oral HRT involving CEE combined with MPA may decrease HbA(1c) levels in women aged 40-49 years and is likely to have no adverse effects on HbA(1c) levels in women older than 50 years.     

Estrogens and lipids. Can HRT designer estrogens, and phytoestrogens reduce cardiovascular risk markers after menopause?

HRT may act preventively to reduce morbidity and mortality from cardiovascular disease in primary prevention. The development of SERMs adds a new, exciting, and promising therapeutic option to this field, as does the enhanced availability of soy phytoestrogen products. Although clinical trial data are incomplete, epidemiologic studies suggest that HRT raises HDL-C and triglyceride levels and lowers LDL-C levels. In addition, HRT lowers levels of Lp(a). These changes account for up to 50% of the cardiovascular risk reduction observed with HRT. In contrast, SERMs have less uniform effects. Both SERMs and phytoestrogens are less potent than HRT but have greater tissue selectivity. Although further study is needed, current information suggests that SERMs and phytoestrogens have significant potential to reduce CAD risk and may be a viable alternative to HRT for modest lowering of lipid levels. Phytoestrogens may be particularly useful for reducing CAD risk in men because they do not cause the side effects associated with estrogen. Additional clinical trials are necessary to determine whether the favorable lipid effects associated with HRT, SERMs, and phytoestrogens are linked to protection against cardiovascular disease. Nonetheless, physicians should consider the use of HRT, SERMs, and phytoestrogens for lowering lipid levels and reducing cardiovascular risk in women.     

Making a decision about ERT/HRT. Evidence to consider in initiating and continuing protective therapy

Alzheimer's disease, CAD, and osteoporosis significantly affect the health and well-being of senior citizens in the United States. The fact that women have a longer life expectancy than men has led to the hypothesis that estrogen in some way imparts protection against these disease processes. Available data on the possible negative effect of estrogen on the development and progression of Alzheimer's disease are provocative but inconclusive. Thus, for the time being, they must remain no more than the basis of an attractive hypothesis. In contrast, available data suggest that ERT and HRT can reduce the risk of CAD, but this effect seems more preventive than therapeutic. Addition of a progestational agent to an estrogen regimen may blunt this effect. Although the medical literature contains very few data that address the issue of duration of therapy, logic would suggest that cessation of therapy would result in the loss of a protective effect. With regard to osteoporosis, ERT and HRT have clear beneficial effects in that they increase BMD and decrease fracture risk. There is good evidence that duration of therapy may be more important than dosage and that these effects rapidly dissipate with cessation of therapy. Finally, as with all medical interventions, ERT or HRT must be individualized for each patient. Although actual health hazards are few, adverse effects are common and the emotion-charged, ever-evolving issue of the negative impact of ERT and HRT on breast cancer risk must always be considered before such therapy is instituted.     

An interesting byproduct of screening: assessing the effect of HRT on arterial calcification in the female breast

Arterial calcification in the female breast (BAC) is a common but unreported finding on breast screening mammograms. Accumulating evidence suggests that BAC may have importance as a marker for generalised vascular disease. In this study, we have assessed the influence of HRT usage on the prevalence of BAC in 4400 women undergoing mammography for breast cancer screening. Significantly increased levels of breast arterial calcification were observed in women who had never used HRT compared with a group of women presently using HRT.     

Histamine release test and measurement of antigen-specific IgE antibody in the diagnosis of allergic conjunctival diseases

Although systemic allergic laboratory tests for the quantification of allergen-specific serum IgE antibody have been widely used, in these tests a high titer of serum specific IgE does not necessarily indicate evidence of allergy. We evaluated the diagnostic value of the glass microfiber-based histamine release test (HRT) using small amounts of whole blood, in 36 cases of allergic conjunctival diseases: 17 cases of allergic conjunctivitis and 19 of atopic keratoconjunctivitis. The patients were evaluated by HRT, capsulated hydrolic carrier polymer (CAP)-RAST, and conjunctival provocation test (CPT) against ten allergens. The positive rates for all allergens were higher in CAP-RAST than in HRT. The mean concordance of HRT with CAP-RAST results was 0.789. The mean concordance of HRT with CPT was 0.892 and that of CAP-RAST with CPT was 0.693. A significantly higher concordance was observed in HRT than CAP-RAST for Japanese cedar and mite antigen. The mean sensitivity, specificity, and efficiency of HRT were higher than those of CAP-RAST. These results indicate that CAP-RAST is good for the screening of allergens and that HRT has an advantage in the confirmation of clinical allergens in allergic conjunctival diseases because of its high sensitivity, specificity, efficiency, and higher concordance with CPT.     

Experience of Postmenopausal Women of Hormone Replacement Therapy

Goal: The purpose of this study was to examine and describe women's physical and psychological changes after a trial of hormone replacement therapy (HRT), so as to be able to provide accurate information about HRT to women who are preparing to undergo HRT. Methods: The study sample consisted of 10 women who were taking hormones for treatment of postmenopausal symptoms. Data were collected from September 2000 to March 2001. Interviews were recorded and transferred to written documents. The analysis of the data used the methodology described by Giogi. Results: The subjects reported that taking HRT was an excellent choice for enhancing their quality of life during menopause because they felt younger and healthier, although they expressed concern about unexpected side‐effects, after their HRT. They felt that such effects could be prevented through regular check‐ups. The participants recommended that all postmenopausal women take HRT because they believed the benefit of HRT was greater than its harmfulness. The subjects also suggested that postmenopausal women need to be educated about the physical and psychological symptoms that they feel during menopause and about how to manage the symptoms. It was concluded that accurate information about the relationship between HRT and the quality of life should be provided to postmenopausal women, in addition to providing educational programs on postmenopausal management to postmenopausal women.     

Hormone replacement therapy in a postmenopausal woman with epilepsy

OBJECTIVE: To prospectively evaluate the effects of hormone replacement therapy (HRT) on seizure activity in a postmenopausal woman with epilepsy. BACKGROUND: Postmenopausal women are at an increased risk for cardiovascular disease and osteoporosis secondary to a lack of estrogen's protective effects. As a result, women without known contraindications often take HRT to counteract this risk. Postmenopausal women with epilepsy are at a greater risk for osteoporosis because of the negative effects that certain antiepileptic drugs have on bone density. Clinical studies and experience have shown that hormonal variances across a woman's lifetime play a significant role in seizure activity, but the effects of HRT in postmenopausal women with epilepsy are unknown. CASE SUMMARY: We report the case of a 51-year-old postmenopausal white woman with epilepsy who presented with frequent vasomotor flushing. To determine individual effects of HRT on seizure activity, therapy was initiated in two three-month phases, with monthly evaluation. A weekly transdermal patch of estradiol 0.1 mg/d was initiated for the first three months. During the second three months, the regimen was expanded to include oral medroxyprogesterone acetate 2.5 mg once daily. Antiepileptic medications and their dosages remained constant. HRT was associated with a decreased incidence of seizures, cessation of vasomotor flushing, improved sleep, and a positive impact on the lipid profile. CONCLUSIONS: This case report describing the prospective addition of HRT in a postmenopausal woman with epilepsy suggests that HRT can be initiated in certain women to achieve therapeutic benefits without adversely affecting seizure activity.     

Hormone replacement: side effects and problems

Profound knowledge of the different activities and side effects of the various types and combinations of HRT regimens is of paramount importance for counseling peri- and postmenopausal women. In this article some practical aspects of different topics concerning HRT such as influence of HRT on blood sugar, diabetes, blood pressure, hypertension, serum lipids, migraine, and progestin intolerance are discussed.     

Hormone replacement therapy (HRT) for hyperlipidemia after menopause

Women are about 10 years older than men to suffer from ischemic heart disease(IHD) and they often experience a sudden rise in cholesterol after menopause. These phenomena are thought to be caused by the production of estrogen in women during normal menstruation cycle and its loss after menopause. Hormone replacement therapy(HRT) has been shown to reduce IHD by nearly 50 per cent. This is caused in part by effects of estrogen on lipid metabolism; it reduces LDL and Lp(a), and increases HDL. Although the first large prospective trial of HRT for secondary prevention of IHD failed to demonstrate estrogen's protective effects, HRT was effective in women with high Lp(a). Thus, selection of patients and HRT regimen seems important.     

Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study

An age-related decline in muscle performance is a known risk factor for falling, fracture and disability. In women, a clear deterioration is observed from early menopause. The effect of hormone replacement therapy (HRT) in preserving muscle performance is, however, unclear. This trial examined the effects of a 12-month HRT and high-impact physical exercise regimen on skeletal muscle in women in early menopause. A total of 80 women aged 50-57 years were assigned randomly to one of four groups: exercise (Ex), HRT, exercise+HRT (ExHRT) and control (Co). The exercise groups participated in a high-impact training programme. The administration of HRT (oestradiol/noretisterone acetate) or placebo was carried out double-blind. Knee extension torque and vertical jumping height were evaluated. Lean tissue cross-sectional area (LCSA) and the relative proportion of fat within the muscle compartment were measured for the quadriceps and lower leg muscles. The ExHRT group showed significant increases in knee extension torque (8.3%) and vertical jumping height (17.2%) when compared with the Co group (-7.2%). Vertical jumping height also increased after HRT alone (6.8%). The LCSA of the quadriceps was increased significantly in the HRT (6.3%) and ExHRT (7.1%) groups when compared with the Ex (2.2%) and Co (0.7%) groups. Lower leg LCSA was also increased in the ExHRT group (9.1%) when compared with the Ex (3.0%) and Co (4.1%) groups. In addition, the increase in the relative proportion of fat in the quadriceps in the Co group (16.6%) was significant compared with those in the HRT (4.9%) and ExHRT (-0.6%) groups. Thus, in post-menopausal women, muscle performance, muscle mass and muscle composition are improved by HRT. The beneficial effects of HRT combined with high-impact physical training may exceed those of HRT alone.     

Cardiovascular risk and hormone replacement therapy in menopause]

Cardiovascular risk associated with hormone replacement therapy (HRT) has been analysed by large epidemiological studies. This treatment has different effects depending on the type of vessel (venous or arterial) or site (heart or brain). The several meta-analyses which have been published conclude that there is a significant decrease of about 30 to 50 per cent in ischaemic heart disease associated with HRT. In addition, oestrogen replacement therapy is associated with a 25 per cent decrease in cardiovascular mortality. A recent meta-analysis has analysed the effect of HRT on cerebrovascular risk. A significant 20 per cent increase in ischaemic stroke associated with the use of HRT has been shown. However, a protective association of about 30 per cent has been observed in haemorrhagic stroke with HRT use. Recent epidemiological studies have suggested an increased risk of thromboembolic disease associated with HRT. The results of a randomized blind placebo-controlled secondary prevention trial have recently been published. In this clinical trial, women who receive oestrogen (0.625 mg conjugated equine oestrogen daily) plus progestin (2.5 mg medroxyprogesterone acetate daily) therapy did not experience a reduction in overall risk of non-fatal myocardial infarction and cardiovascular heart disease death. This treatment also significantly increases the rate of thromboembolic events. Other randomized trials of HRT for primary prevention are scheduled to yield results by 2000 or 2005. All these studies have been conducted essentially in Anglo-Saxon countries and have analysed the effects of conjugated equine oestrogens alone or combined with medroxyprogesterone acetate. This treatment is not currently used in France. But no randomized trials are under way with the HRT common in France (transdermic oestrogen combined with natural progesterone). The effects of this treatment on cardiovascular disease remain unknown.     

Hypnotic Relaxation Therapy for Reduction of Hot Flashes in Postmenopausal Women: Examination of Cortisol as a Potential Mediator

Hypnotic relaxation therapy (HRT) has been shown to reduce hot flashes in postmenopausal women and breast cancer survivors. While the biological mechanism by which HRT reduces hot flashes is unknown, it has been speculated that reduction of stress mediates the intervention’s effectiveness. The purpose of the present study was to examine the effect of HRT on a known biomarker of stress (cortisol) and changes in cortisol as a mediator. Sixty-two postmenopausal women received hypnotic relaxation therapy for hot flashes and completed measures of hot flashes in addition to providing cortisol samples at baseline and endpoint. HRT resulted in significantly decreased early evening salivary cortisol concentrations. However, changes in salivary cortisol concentrations did not mediate the effects of HRT.     

Heart rate turbulence and heart rate variability in patients with atrial synchronous ventricular pacing

Background: Heart rate turbulence (HRT) and heart rate variability (HRV) have been shown to be independent and powerful predictors of mortality in a specific group of cardiac patients. Pacing has unfavorable effects on autonomic function. Our aim is to investigate autonomic responses to atrial synchronous ventricular pacing (VDD) by evaluating HRT and HRV parameters.
Methods and Results: The study groups comprised 12 control and 12 patients without organic heart disease and with normal sinus function who were implanted with a permanent VDD pacing system for high-degree atrioventricular block. The HRV and HRT analysis were assessed from a 24-hour Holter recording. There was no statistically significant difference between the two groups for HRV parameters. When HRT parameters were compared, turbulence onset was significantly higher in the cardiac paced group than the controls group (2.729 ± 8.818 vs –1.565 ± 8.301, P = 0.006), but no statistically significant difference was found between the two groups for turbulence slope (11.166 ± 10.034 vs 31.675 ± 28.107, P = 0.68). The number of patients who had abnormal HRT onset was significantly higher in the paced group than controls (9 vs 2, P = 0.004).
Conclusion: Atrial synchronous pacing has unfavorable effects on autonomic function. Altered ventricular depolarization sequence may lead to changes in autonomic response. Although we found no difference in HRV parameters between the control and VDD patient groups, the HRT onset and number of patients with abnormal HRT onset was significantly higher in VDD patients. HRT onset can be a better way of noninvasive autonomic response predictor in VDD patients.     

Menopause

The body of evidence now swings the scale toward the benefit of HRT for women beginning at the menopause. Based on newer studies, the risks for osteoporosis, cardiovascular morbidity, breast carcinoma, symptomatic vasomotor and anatomic changes occurring postmenopausally outweigh the risks of hormone replacement therapy in the end of the 20th century. Women should be instructed in adequate calcium intake, 1000 mg per day premenopausally and 1500 mg per day postmenopausally. Osteoporotic, breast carcinoma, and cardiovascular risks should be investigated at age 35 with appropriate lab screening, including lipoprotein analysis. Screening mammography should begin at age 40, continuing every 5 years until age 50, and yearly between ages 50 and 65. A diet high in calcium, low in cholesterol and fat, and a weight reduction program should be made available as early as possible and continued indefinitely. HRT should be made available beginning at menopause and continued to age 70. Moderate exercise should be encouraged at all ages. The next 5 to 10 years will answer some of the questions about the benefits of long-term HRT postmenopausally, especially with respect to its influence on cardiovascular risk. New progestational agents will probably be developed that will have fewer adverse effects on lipid profiles, while maintaining the protective effect on the endometrium and breast and further influencing the benefits of HRT postmenopausally. Modern medicine certainly cannot ensure living forever. The body of knowledge now available can modify the major causes for morbidity and mortality as the baby boom population reaches their middle age and golden years.