Long-term Estrogen Therapy Research Articles

7 Hormone replacement therapy

Oestrogen deficiency at the menopause leads to bone loss primarily as a result of increased bone turnover and an increase in the activity of osteoclasts. Hormone replacement therapy (HRT) reverses these changes, preventing menopausal bone loss and reducing fracture risk at the spine, hip, and wrist, although the magnitude of this reduction has not been accurately established. The optimal duration of therapy for the prevention of osteoporosis is uncertain but there is increasing evidence that life-long treatment after the menopause may be required to maintain maximum protection against fracture. The extraskeletal effects of long-term oestrogen therapy include protection against cardiovascular disease and a possible increase in the risk of breast cancer; the persistence of these effects after therapy is withdrawn is uncertain although there is some evidence that the increase in risk of breast cancer is seen only in current users. Furthermore, there is increasing evidence that the use of progestogens in combined formulations does not substantially alter either the cardiovascular benefits or the increased risk of breast cancer, although further studies are needed in this area. The emergence of 'no-bleed' preparations in recent years has increased the acceptability of HRT for some women, particularly those in older age groups. Finally, the development of tissue-selective oestrogen agonists is an exciting advance which may enable life-long therapy after the menopause to protect against cardiovascular and bone disease in the absence of significant side-effects.

Effect of estrogens on bone and other systems and hormonal substitute treatment.

This article reviews recent advances in the effects of estrogen on bone and other body systems. The effect of estrogen use for the prevention of osteoporosis is no longer a matter of debate. Some issues are still discussed, however, especially with regard to the magnitude of its protection (especially for hip fracture), which would be dependent on the time at which estrogen therapy is initiated with respect to menopause as well as its total duration of use. The mechanisms of estrogen's action on bone also remains poorly understood. Controversy persists concerning the specific contribution of an indirect action through the modulation of calciotropic hormones and a direct action on bone cells in which estrogen receptors have been identified. Estrogens have been shown to reduce osteoclastogenesis by modulating the production of cytokines (interleukins, tumor necrosis factor) and transforming growth factor from bone marrow and bone cells. In addition to its effects on bone, a great number of observational studies have evaluated the relationship between estrogen use and coronary heart disease. The overall risk of coronary disease is estimated to be reduced by 50% in women who use estrogen replacement therapy. This reduction would be even greater in women with previous atherosclerosis. Moreover, recent data suggest that estrogen use could be associated with delayed onset and reduced risk for Alzheimer's disease. Overall, estrogen treatment in postmenopausal women has several proven benefits. Conversely, the potential risks of long-term estrogen therapy include a slightly increased risk of breast cancer, which would be associated with long-term use. Although the individual decision for a postmenopausal woman to start estrogen replacement therapy must take into account this risk:benefit ratio, current evidence suggests a clear advantage for estrogen's benefits over its risks.

Long-Term Estrogen Therapy Improves Vascular Function in Male to Female Transsexuals

Objectives. This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women.Background. Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied.Methods. We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound.Results. Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean ± SE] 11.5 ± 1.3% and 9.4 ± 1.1% vs. 5.2 ± 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 ± 1.7% and 21.0 ± 0.9% vs. 14.5 ± 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 ± 0.12 and 1.82 ± 0.11 mmol/liter vs. 1.35 ± 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 ± 0.2 nm vs. 26.2 ± 0.1 and 26.6 ± 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (rs= −0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2= 0.3, p < 0.005).Conclusions. Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.(J Am Coll Cardiol 1997;29:1437–44)

Arterial Reactivity Is Enhanced in Genetic Males Taking High Dose Estrogens

Objectives. We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males.Background. Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown.Methods. We studied the arterial physiology of 30 genetic males—15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject.Results. Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [±SD] 7.1 ± 3.1% vs. 3.2 ± 2.8%, p = 0.001), as was the GTN response (21.2 ± 6.7% vs. 14.6 ± 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03).Conclusions. Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.(J Am Coll Cardiol 1997;29:1432–6)

EFFECTS OF OESTROGEN AND PROGESTERONE ON AGE‐RELATED CHANGES IN ARTERIES OF POSTMENOPAUSAL WOMEN

1. Hormone replacement therapy (HRT) with oestrogen or oestrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima-medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non-HRT) and those women on long-term HRT with oestrogen alone (HRT-E) or oestrogen plus progestin (HRT-EP). 2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure. 3. Plasma total cholesterol was reduced and high-density lipoprotein-cholesterol was increased in the HRT group compared with the non-HRT group; low-density lipoprotein-cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT-E and HRT-EP subgroups were similar. 4. Carotid IMT was significantly reduced in the HRT group compared with men and non-HRT groups. Results for HRT-E and HRT-EP subgroups were similar. 5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age; SAC was higher in both HRT-E and HRT-EP groups compared with the non-HRT group. Indices of carotid stiffness were similar in men and in non-HRT groups. The HRT-EP group showed increased carotid stiffness compared with the HRT-E group. 6. There is an apparent protective effect of long-term oestrogen therapy on carotid IMT and age-related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.

Long-term estrogen therapy abolishes acute estrogen-induced coronary flow augmentation in postmenopausal women

Postmenopausal estrogen replacement therapy (ERT) may reduce the clinical manifestations of coronary heart disease by favorably modulating coronary vasoreactivity. Intravenous ethinyl estradiol acutely increases coronary flow in postmenopausal women not receiving ERT. Because several vasoactive agents induce vasomotor tolerance when administered on a long-term basis, we hypothesized that long-term ERT attenuates the acute coronary vasomotor effects of intravenous ethinyl estradiol. To test this hypothesis, coronary hemodynamics were determined before and 15 minutes after intravenous ethinyl estradiol (35 μg) in 10 postmenopausal women who were receiving long-term conjugated ERT (group 1) and 10 who had never received ERT (group 2). Estradiol administration in group 1 was not associated with significant changes in coronary flow or resistance. However, women in group 2 exhibited a 28.6% ± 6.5% ( p < 0.001) increase in coronary flow and a 19.9% ± 3.5% ( p = 0.008) decrease in resistance. These results demonstrate that long-term ERT significantly attenuates the response of coronary arteries to the acute vasomotor effects of a high dose of estradiol. This response may be caused by long-term estrogen-induced coronary flow augmentation or to the development of vasomotor tolerance to estrogen. (Am Heart J 1997;133:323-8.)

Long-Term Postmenopausal Estrogen Therapy May Be Associated with Increased Risk of Breast Cancer

Long-Term Postmenopausal Estrogen Therapy May Be Associated with Increased Risk of Breast Cancer

Estrogen Replacement Therapy After Coronary Angioplasty in Women

Objectives. The purpose of this study was to assess the effects of estrogen replacement therapy on long-term outcome, including restenosis, myocardial infarction, stroke and death after a first percutaneous transluminal coronary angioplasty (PTCA) procedure, in postmenopausal women.Background. Observational and epidemiologic studies, basic laboratory research and clinical trials consistently suggest that estrogen replacement therapy is associated with beneficial cardiovascular effects in women. These cardioprotective actions may be particularly relevant to women with coronary artery disease, such as those who have undergone PTCA.Methods. This was a retrospective study that included 337 women who underwent elective PTCA between 1982 and 1994. The treatment group consisted of 137 consecutive women receiving long-term estrogen therapy at the time of elective PTCA and during follow-up. The control group comprised 200 women who were computer-matched with the estrogen group. The mean follow-up period was 65 ± 35 months.Results. Actuarial survival was superior in the estrogen group; the 7-year survival rate was 93% for the estrogen group versus 75% for the control group (p = 0.001). The cardiovascular event rate (death, nonfatal myocardial infarction or nonfatal stroke) was significantly lower in the estrogen group at 7 years (12% vs. 35% in the control group, p = 0.001). The need for subsequent revascularization during follow-up was similar in the two groups. Multivariable analysis identified diabetes, estrogen therapy (adjusted risk ratio 0.38, 95% confidence interval 0.19 to 0.79) and left ventricular ejection fraction <40% as independent correlates of cardiovascular death or myocardial infarction during follow-up.Conclusions. Estrogen replacement therapy was associated with an improved long-term outcome after PTCA in postmenopausal women.(J Am Coll Cardiol 1997;29:1–5)>

"Reduced Mortality Associated with Long-term Postmenopausal Estrogen Therapy."

Objective To compare all-cause and specific-cause mortality rates in women who had or had not used long-term postmenopausal estrogen replacement therapy (ERT). Methods We identified women who used long-term postmenopausal ERT and compared them with a sample of age-matched postmenopausal nonusers. Through linking of these subjects' medical record numbers to various data bases, we examined survivorship and cause of death among estrogen users and nonusers. The risk of death in 232 postmenopausal women who began ERT within 3 years of menopause and used it for at least 5 years was compared with that of 222 age-matched postmenopausal nonusers. In the users, the mean length of estrogen use was 17.1 years. Results Statistically significant reductions in all-cause mortality were found in users compared with nonusers. For death from any cause, the age-adjusted relative risk (RR) and associated 95% confidence interval (CD in estrogen users was 0.54 (0.38–0.76). The reduction in all-cause mortality was largely due to reductions in coronary heart disease (RR 0.40, CI 0.16–1.02) and other cardiovascular disease (RR 0.27, CI 0.10–0.71). Overall cancer mortality was similar in the two groups (RR 0.85, CI 0.46–1.58), although estrogen users had a higher risk of death from breast cancer (RR 1.89, CI 0.43–8.36) and lower risk of death from lung cancer (RR 0.22, CI 0.04–1.15). Conclusion Long-term ERT use is associated with lower all-cause mortality and confers this apparent protection primarily through reduction in cardiovascular disease.

Calcium supplements increase bone mineral density in women with low serum calcium levels during long-term estrogen therapy.

In order to clarify whether the long-term effect of estrogen on bone mineral density (BMD) is reinforced by low dose calcium supplements, 600-800 mg of calcium lactate was administered to postmenopausal or oophorectomized women who had been undergoing unopposed estrogen therapy for at least 2 years and whose serum calcium level was suppressed to below the normal range. To patients whose serum calcium levels had been within the normal range, the same dose of estrogen alone was continued. Changes in lumbar spine BMD before and after calcium supplementation was measured by dual-energy X-ray absorptiometry. Lumbar spine BMD decreased by -0.37% for 2 years in women treated with estrogen alone, while that of women treated with estrogen and calcium increased by 2.78% (P = 0.003). These results indicate that low dose calcium supplements potentiate the effect of estrogen in women with decreased serum calcium during long-term hormone replacement therapy.

Reduced mortality associated with long-term postmenopausal estrogen therapy

To compare all-cause and specific-cause mortality rates in women who had or had not used long-term postmenopausal estrogen replacement therapy (ERT). We identified women who used long-term postmenopausal ERT and compared them with a sample of age-matched postmenopausal nonusers. Through linking of these subjects' medical record numbers to various data bases, we examined survivorship and cause of death among estrogen users and nonusers. The risk of death in 232 postmenopausal women who began ERT within 3 years of menopause and used it for at least 5 years was compared with that of 222 age-matched postmenopausal nonusers. In the users, the mean length of estrogen use was 17.1 years. Statistically significant reductions in all-cause mortality were found in users compared with nonusers. For death from any cause, the age-adjusted relative risk (RR) and associated 95% confidence interval (CI) in estrogen users was 0.54 (0.38-0.76). The reduction in all-cause mortality was largely due to reductions in coronary heart disease (RR 0.40, CI 0.16-1.02) and other cardiovascular disease (RR 0.27, CI 0.10-0.71). Overall cancer mortality was similar in the two groups (RR 0.85, CI 0.46-1.58), although estrogen users had a higher risk of death from breast cancer (RR 1.89, CI 0.43-8.36) and lower risk of death from lung cancer (RR 0.22, CI 0.04-1.15). Long-term ERT use is associated with lower all-cause mortality and confers this apparent protection primarily through reduction in cardiovascular disease.

Benefit/risk of estrogen therapy in cardiovascular disease: current knowledge and future challenges.

In the United States, cardiovascular disease represents the leading cause of death among women. A majority of the deaths are due to coronary disease. In addition, the incidence of heart attacks increases with age. Among those who are 65 years of age or older, the estimated heart attack rate is 374,000 per year for women, compared with 440,000 per year for men. In the past three decades, a number of observational studies have suggested that estrogen therapy can reduce the risk of coronary disease in postmenopausal women. This protective effect appears to be much greater in women who have existing coronary disease. These observational data point to the potential usefulness of estrogen therapy in preventing cardiovascular death among women. Although large, well-controlled, clinical trials are needed to confirm the benefit of estrogen therapy, several important findings strongly support the cardioprotective effect of estrogen therapy. For example, in monkeys estrogen prevents the accumulation of low-density lipoprotein (LDL) cholesterol (a known risk factor for heart disease) in coronary arteries, and estrogen has also been shown to increase high-density lipoprotein (HDL) cholesterol (a known cardioprotective factor). Estrogen also possesses a vasodilating property, which can improve cardiac performance in ischemic heart disease. In addition, recent studies have demonstrated that estrogens (especially equilin) exhibit a high antioxidant effect, which may also be related to cardioprotectivity. Although estrogen therapy has been observed to decrease the risk of coronary disease, long-term estrogen therapy has also been found to increase the risk of uterine carcinoma; the addition of progesterone to estrogen therapy may lessen this undesirable risk, however. On the other hand the addition of progesterone to estrogen therapy may decrease estrogen's beneficial effect on HDL cholesterol. What should be the present position on estrogen therapy in postmenopausal women? What is the best dosage regimen? Should it be used alone or in combination with a progesterone? These important issues are discussed, as are several current clinical trials addressing the issue of estrogen therapy in postmenopausal women.

Epidemiology of the rheumatic diseases.

Epidemiologic studies are important for both understanding and defining rheumatology practice. Controversy still exists over whether the incidence of rheumatoid arthritis is declining, and genetic studies indicate a diversity of HLA haplotypes in rheumatoid arthritis. Large longitudinal osteoarthritis studies have helped define diagnostic criteria and the role of obesity in disease progression. The negative association between osteoarthritis and osteoporosis at specific sites continues to be explored, and the value of long-term estrogen therapy in preventing bone loss has been examined. Both retrospective and prospective population studies have been used to describe the relationship between silicone gel breast implants and connective tissue disease. These and other studies have helped to define the important role of epidemiologic research in the understanding of rheumatic diseases.

The Waning Effect of Postmenopausal Estrogen Therapy on Osteoporosis

Almost all physicians and their patients believe that estrogen treatment can prevent osteoporosis. Evidence from the Framingham Study reported in this issue of the Journal supports this hypothesis1. In women less than 75 years old who had received long-term estrogen therapy, bone mineral density was higher than in women who had never taken estrogen. In women more than 75 years old, however, there was little difference in bone density between women who had taken estrogen and those who had not. How can we reconcile these results with what is known about the effect of estrogen on the risk of . . .

Review: Long-term estrogen therapy increases the risk for breast and endometrial cancer but decreases the risk for coronary heart disease and hip fracture in postmenopausal women in primary prevention trials

Source Citation Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992 Dec 15;117:1016-37.

Transvaginal Sonographic Evaluation of Prostatitis in a Transsexual

A transsexual (male to female) patient reported a 1-month history of pelvic pain. After an unsuccessful transvesical pelvic ultrasound examination, a transvaginal ultrasound examination was attempted through the surgically formed vagina. The utility and indications of this route of examination in transsexuals, as well as the changes that develop in the prostate of patients who receive long-term estrogen therapy, are discussed.

Hormone therapy to prevent disease and prolong life in postmenopausal women.

To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong life. Review of the English-language literature since 1970 on the effect of estrogen therapy and estrogen plus progestin therapy on endometrial cancer, breast cancer, coronary heart disease, osteoporosis, and stroke. We used standard meta-analytic statistical methods to pool estimates from studies to determine summary relative risks for these diseases in hormone users and modified lifetable methods to estimate changes in lifetime probability and life expectancy due to use of hormone regimens. There is evidence that estrogen therapy decreases risk for coronary heart disease and for hip fracture, but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase in risk for breast cancer. The increase in endometrial cancer risk can probably be avoided by adding a progestin to the estrogen regimen for women who have a uterus, but the effects of combination hormones on risk for other diseases has not been adequately studied. We present estimates for changes in lifetime probabilities of disease and life expectancy due to hormone therapy in women who have had a hysterectomy; with coronary heart disease; and at increased risk for coronary heart disease, hip fracture, and breast cancer. Hormone therapy should probably be recommended for women who have had a hysterectomy and for those with coronary heart disease or at high risk for coronary heart disease. For other women, the best course of action is unclear.

The benefits and risks of hormone replacement therapy: An epidemiologic overview

In postmenopausal women estrogens alone are effective in reversing vasomotor symptoms and vaginal atrophy. They also prevent the bone loss associated with osteoporosis and reduce the risk of cardiovascular disease, probably through their beneficial effects on lipid metabolism. Unopposed long-term estrogen therapy, however, increases the risk of developing endometrial hyperplasia, endometrial cancer, and possibly breast cancer as well. The risk of developing endometrial cancer can be reduced by combining a progestin with the estrogen, by controlling obesity, and by rigorous clinical screening and surveillance. The effect of progestins on the risk of developing breast cancer is still controversial. Although some progestins may reverse the cardioprotective effect of estrogens, those with minimal androgenicity appear less likely to do so. Hormone replacement therapy that combines estrogen with a progestin of minimal androgenicity is thus a rational alternative to unopposed estrogen therapy. Current epidemiologic knowledge suggests that the benefits of hormone replacement therapy, with or without any progestins, strongly outweigh the risks.

Evaluating the benefits and risks of postmenopausal hormone therapy

The evidence that estrogen protects against coronary heart disease is biologically plausible, consistent, and strong. These benefits have not been established by a randomized trial, however, so that the degree of protection against heart disease might have been overestimated because estrogen users tend to be healthier than nonusers. A randomized trial to determine whether estrogen alone or in combination with progestin protects against coronary heart disease should be given a high priority. Progestins generally attenuate the effects of estrogen on the concentrations of HDLC. It is not known whether this effect also limits the beneficial effects of estrogen on the risk of coronary heart disease. Recent studies suggest that estrogen may protect against coronary heart disease in other ways besides favorably altering serum concentrations of lipoproteins and that progestins might not have adverse effects on the risk of heart disease. Currently, theoretical concerns that progestins might be harmful seem outweighed by the evidence that they protect against endometrial cancer in women who have a uterus. For these women, some may find the side effects of progestins to be so bothersome that they prefer to take estrogen alone. This approach is reasonable so long as the patient has periodic endometrial biopsies for early detection of pre-malignant or malignant endometrial changes. Women without a uterus should take estrogen alone. Women who take long-term estrogen therapy appear to have about a 30% greater chance of developing breast cancer. On the other hand, breast cancer that develops while taking estrogen therapy might have a slightly better prognosis. Quantitative comparisons of fatal conditions suggest that the benefits of long-term therapy outweigh the risks. But these comparisons assume that all causes of deaths are equally important and do not adequately take account of other psychologic and physical effects of hormone therapy. Densitometry may be valuable for a woman who would not take long-term hormone therapy unless she knew that her bone density was low. Densitometry should not substitute for consideration of and counseling about the other risks and benefits of hormone therapy besides prevention of fracture. Physicians can provide useful information and make influential recommendations about hormone therapy. However, since an individual woman gains the benefits and suffers the consequences of treatment, her preferences should be respected. Ideally, the decision about hormone therapy should be based on the patient's informed preference.

Hepatic Involvement in Hereditary Hemorrhagic Telangiectasia

Hepatic Involvement in Hereditary Hemorrhagic Telangiectasia