Hormone replacement therapy in postmenopausal women

From the endocrine point of view, menopause is considered a deficiency state and menopausal hormone replacement therapy (HRT) regarded as restoring the premenopausal endocrine milieu. Millions of healthy postmenopausal women were taking HRT in late 1990's many in the absence of menopausal symptoms. The major benefit from HRT was considered to be cardiovascular protection and also protection against osteoporosis and Alzheimer's Disease. The Women's Health Initiative (WHI) trial and other studies published since 2002 fundamentally changed our understanding of risks and benefits associated with HRT. This review discusses the effects of HRT on menopausal symptoms, cognitive function, cardiovascular disease, osteoporosis and also breast and bowel cancer.     

Hormone replacement therapy is associated with higher FEV1 in elderly women

Estrogen and progesterone use have been associated with improved pulmonary function in premenopausal women. However, little research has examined the relationship between hormone replacement therapy (HRT) and pulmonary function in postmenopausal women. We examined the relationship of HRT with spirometry in 2,353 women aged 65 yr and older participating in the Cardiovascular Health Study in 1993/1994. Current use of HRT was hypothesized to be associated with higher FEV1, higher FVC, and less pulmonary obstruction (FEV1/FVC < 65%). FEV1 was higher among current HRT users compared to noncurrent users in the following groups: overall (1.82 L versus 1.66 L, p < 0.0001), among women without asthma (1.85 L versus 1.69 L, p < 0.0001), among former smokers (1.76 L versus 1.60 L, p = 0.013), and among never smokers (1.90 L versus 1.72 L, p < 0.0001). Overall, HRT use was associated with a lower prevalence of pulmonary obstruction (OR 0.75 [95% CI 0.55, 0.99]). After controlling for potential confounders, HRT use was significantly associated with higher FEV(1) (p = 0.031) and with a lower prevalence of obstruction (OR 0.67 [95% CI 0.48, 0.95]). We conclude that postmenopausal women who use HRT have higher levels of FEV1 and less obstruction, which could not be explained by their lower rates of smoking and other health factors associated with HRT use.     

Hormone replacement therapy and inflammation: interactions in cardiovascular disease

Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-beta, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.     

Hormone replacement therapy in women with rheumatic diseases

Hormone replacement therapy (HRT) for the treatment of menopausal symptoms and for the prevention of osteoporosis and cardiovascular diseases has clearly increased during the last decades. Women with rheumatic diseases, especially when using corticosteroids, are in a high risk of osteoporotic fractures and atherosclerotic disease, which cause significant morbidity and mortality in later life. In this review, the benefits and risks of HRT in postmenopausal women are reviewed in general and, in particular, in women with rheumatic diseases.     

Hormone replacement therapy and cardiovascular risk in menopausal women

The incidence of cardiovascular disease (CVD) differs markedly with regard to gender and age. Women have CVD 10 years later than men. Estrogen seems to play a key role in mediating the risk of CVD in women. The relative risk of CVD is lower in women before menopause and equals that of men between the 6th and 7th decade. However the effects of hormone replacement therapy (HRT) on cardiovascular morbidity and/or mortality in postmenopausal women remain controversial. The results of observational studies and randomized trials in post menopausal women are reviewed in this article. They point out the absolute need of large scale prospective randomized clinical studies to quantify the effects of HRT for primary and secondary prevention of cardiovascular disease in particular in non American countries.     

Coronary heart disease in women: Hormone replacement therapy

Opinion statement  

Hormone replacement therapy and associated risk of stroke in postmenopausal women

BACKGROUND: There is little information about the risk of stroke in relation to time since initiation of hormone therapy and in relation to estrogen dose. METHODS: We conducted a population-based case-control study at Group Health Cooperative (GHC), a health maintenance organization in the greater Seattle (Wash) area, to assess the association of hormone replacement therapy with the risks of incident ischemic and hemorrhagic stroke. Cases were all postmenopausal women with incident stroke at GHC during July 1989 through December 1998 (726 ischemic strokes and 213 hemorrhagic strokes). Controls were randomly selected from GHC enrollees and frequency matched to cases on age and calendar year (n = 2525). Hormone use was assessed from computerized pharmacy data. We reviewed the medical record to confirm eligibility and assess other risk factors. RESULTS: After risk factor adjustment, ischemic stroke was not associated with current use of estrogen with progestin (odds ratio [95% confidence interval]: 0.97 [0.69-1.37]) or without (0.94 [0.72-1.23]) compared with never use. Similarly, hemorrhagic stroke was not associated with current use of estrogen with progestin (0.74 [0.43-1.28]) or without (1.06 [0.71-1.56]). However, the risks of ischemic stroke and hemorrhagic stroke were increased 2-fold during the first 6 months of hormone use (ischemic stroke: 2.16 [1.04-4.49], hemorrhagic stroke: 2.20 [0.83-5.81]). Risk of ischemic stroke also increased with estrogen dose (P for trend =.03). CONCLUSION: The transitory increase in risks of ischemic stroke and hemorrhagic stroke associated with initiation of hormone replacement therapy merits further investigation.     

Hormone replacement therapy in women with previous breast cancer.

As breast cancer is known to be a tumour sensitive to the effects of endogenous oestrogens, clinicians are reluctant to prescribe hormone replacement therapy (HRT) to women with a history of previous breast cancer for fear of stimulating disease recurrence, and it is currently contraindicated in this group of women. However, an increasing proportion of breast cancer patients are requesting the use of HRT to relieve the symptoms of oestrogen deficiency, which are also a common side-effect of adjuvant therapy for breast cancer. Observational data on the use of HRT in breast cancer survivors has not demonstrated an increase in disease recurrence, but uncertainty will continue in the absence of data from prospective, randomized trials. This review aims to demonstrate why it is ethical and scientifically important to undertake such studies.     

Hormone replacement therapy

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, the results of recent large scale clinical studies in the U.S. indicate that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. According to these studies, the benefit of HRT does not outweigh its risk except the treatment of postmenopausal vasomotor symptoms. To resolve this problem, low dose HRT and SERM (selective estrogen receptor modulator) regimens are under investigation.     

Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women

BACKGROUND: The incidence of hypertension in postmenopausal women exceeds that in age-matched men. Longitudinal studies relating hormone replacement therapy (HRT) to blood pressure changes are sparse. OBJECTIVE: To investigate the association between HRT and longitudinal changes in blood pressure in postmenopausal women. DESIGN: Longitudinal observational study. SETTING: Community-dwelling volunteers. PATIENTS: 226 healthy, normotensive postmenopausal women from the Baltimore Longitudinal Study of Aging with a mean (+/-SD) age of 64 +/- 10 years were followed for 5.7 +/- 5.3 years. Seventy-seven women used both estrogen and progestin, and 149 used neither. MEASUREMENTS: Lifestyle variables, blood pressure, and traditional cardiovascular risk factors were measured at baseline and approximately every 2 years thereafter. RESULTS: Systolic blood pressure at baseline was similar in HRT users and nonusers (133.9 +/- 16.0 mm Hg vs. 132.4 +/- 14.8 mm Hg). Over time, average systolic blood pressure increased less in HRT users than nonusers, independent of other cardiovascular risk factors, physical activity, and alcohol use. For example, HRT users who were 55 years of age at their first Baltimore Longitudinal Study of Aging visit experienced a 7.6-mm Hg average increase in systolic blood pressure over 10 years; in contrast, the average increase in nonusers was 18.7 mm Hg. The lesser increase in systolic blood pressure in HRT users was more evident at older age. Diastolic blood pressure, which did not change statistically over time in either group, was not associated with HRT. CONCLUSION: Postmenopausal women taking HRT have a smaller increase in systolic blood pressure over time than those not taking HRT. This difference is intensified at older ages.     

Estrogen replacement therapy and colorectal cancer risk in elderly women

PURPOSE: Colorectal cancer is the fourth most common incident cancer in the United States and causes more cancer deaths than any site except lung. Twenty-two epidemiologic studies have examined the relationship of estrogen replacement therapy and colon and rectal cancers with inconsistent results. However, recent studies suggest a reduced risk among current users. The purpose of the present study was to analyze the Leisure World Cohort for possible association of estrogen replacement therapy with colorectal cancer risk. METHODS: A cohort of 7,701 female members who were initially free of cancer and self-reported their use of estrogen replacement therapy were followed up from June 1981 through December 1995 for development of colorectal cancer. RESULTS: We observed 249 incident colorectal cancer cases and 89 colorectal cancer deaths. Women who had used estrogen replacement therapy had an age-adjusted colorectal cancer incidence rate of 2.67 per 1,000 person-years compared with 3.30 per 1,000 personyears among lifetime nonusers (relative risk =0.81; 95 percent confidence interval, 0.63 to 1.04). Among recent users the incidence was one-third lower than among lifetime nonusers (relative risk =0.66; 95 percent confidence interval, 0.44 to 0.98). Risk did not differ by duration of estrogen replacement therapy, usual dose of conjugated estrogen, or route of estrogen administration. The effects of current estrogen replacement therapy on colon cancer incidence (relative risk =0.70; 95 percent confidence interval, 0.45 to 1.09), right-sided colon cancer incidence (relative risk =0.75, 95 percent confidence interval, 0.38 to 1.48), left-sided colon cancer incidence (relative risk =0.76; 0.76; 95 percent confidence interval, 0.41 to 1.41), rectal cancer incidence (relative risk =0.52; 95 percent confidence interval, 0.21 to 1.31), and colorectal cancer mortality (relative risk =0.82; 95 percent confidence interval, 0.44 to 1.54) were similar. CONCLUSION: A reduced risk of colorectal cancer may be an additional benefit of recent estrogen replacement therapy use, which should be considered by postmenopausal women when deciding whether to use hormones.This research was funded by grants from the National Institutes of Health (CA32197), the Earl Caroll Trust Fund, and Wyeth-Ayerst Laboratories.Presented at the annual meeting of the Pacific Coast Fertility Society, Indian Wells, California, April 22 to 26, 1998.     

Hormone replacement therapy and arterial blood pressure in postmenopausal women with hypertension

BACKGROUND: Data on the effect of hormone replacement therapy (HRT) on blood pressure (BP) in hypertensive menopausal women are limited. OBJECTIVE: To investigate the association between HRT and longitudinal change in BP in hypertensive menopausal women. PATIENTS AND METHODS: We recruited a total of 161 hypertensive menopausal women (mean age = 52.2 +/- 6.6 years) attending the hypertension clinic in our hospital that requires HRT to attenuate the effect of menopause symptoms. These women were followed for up tp 36 months, being evaluated every 6 months with measurements of their BP, weight and the number of drugs needed to control their BP. We also measured serum cholesterol levels before and after the initiation of HRT. RESULTS: The systolic BP remained unaffected throughout the whole follow-up period, whereas the diastolic BP was slightly reduced at 6, 24 and 36 months. This decrease was accompanied by an increased need for antihypertensive medication throughout the entire follow-up period, while the body weight also increased at 18, 24, and 36 months. No particular differences were noted with respect to ethnicity, history of pre-eclampsia or surgical menopause, before and after the initiation of HRT. Serum cholesterol levels remained unchanged during the evaluation period. Oestrogen-progestogen combination therapy use was associated with a lower diastolic BP and a smaller number of antihypertensive drugs compared to other forms of HRT. CONCLUSION: HRT use does not have an adverse gross effect on BP in hypertensive menopausal women who need it, although there may be an increased need for antihypertensive therapy during the 36-moth follow-up period of our study.     

Hormone replacement therapy enhances postprandial lipid metabolism in postmenopausal women.

Postmenopausal estrogen therapy reduces cardiovascular morbidity and mortality, except in women with advanced coronary disease. This beneficial effect is partly attributed to a reduction of fasting plasma total and low-density lipoprotein cholesterol (LDL-C) and an elevation of plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Since postprandial lipemia seems to play a role in the pathogenesis of coronary artery disease, we evaluated the effect of hormone replacement therapy (HRT) on postprandial lipoprotein metabolism in 14 normolipemic postmenopausal women. A vitamin A fat-loading test before and after three cycles of treatment with a sequential combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) was used to label chylomicrons and chylomicron remnants with retinyl palmitate (RP), and RP clearance was assessed over an 8-hour period postprandially. Following 3 months of HRT, fasting total cholesterol and LDL-C levels were reduced 9.8% (P = .049) and 16.5% (P = .023), respectively. Fasting HDL-C levels increased 18.9% (P = .001). Fasting triglycerides (TGs) increased, but not significantly. Postprandial integrated plasma TGs did not change significantly. The integrated RP levels in whole plasma and chylomicron (Svedberg flotation units [Sf] > 1,000) and nonchylomicron (Sf < 1,000) fractions were reduced 58% (P = .043), 78% (P = .041), and 75% (P = .001), respectively, after hormonal treatment. Enhanced clearance of chylomicrons and chylomicron remnants by HRT may contribute to the protective effect of estrogens against cardiovascular disease in normolipemic postmenopausal women.     

Hormone replacement therapy and ischaemic heart disease among postmenopausal women.

The beneficial effect of hormone replacement treatment (HRT) on osteoporosis and menopausal symptoms has been well documented in randomised trials, but the impact of oestrogen-mediated metabolic changes on the risk of ischaemic heart disease (IHD) is still debated. Randomised studies have shown that HRT increases levels of high-density lipoprotein cholesterol while causing a reduction in the levels of low-density lipoprotein cholesterol, serum fibrinogen, plasminogen activator inhibitor and homocysteine. In addition, HRT increases insulin sensitivity in both normoglycaemic and diabetic women. Unlike oral contraceptives, HRT has not been associated with an increase in arterial blood pressure, whereas a small increase in the risk of breast cancer and of venous thromboembolism appears to occur with both treatments. Interestingly, some data suggest that oestrogen preparations may have different effects on lipids. For instance, the beneficial effect on cholesterol metabolism observed with oral conjugated oestrogen does not occur with transdermal oestradiol, suggesting that the first-pass effect through the portal circulation may be necessary to achieve the full metabolic effect of oestrogen treatment. Nevertheless, although a wealth of observational studies show that HRT is associated with a significant reduction in morbidity and mortality from IHD, the only randomised data available to date do not support these findings in postmenopausal women with established coronary artery disease.