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One of the most complex health care decisions facing women is whether to use postmenopausal HT. Once prescribed primarily to relieve vasomotor symptoms, HT has been promoted as a strategy to forestall various disorders that accelerate after menopause, including osteoporosis and cardiovascular disease. In 2000, nearly 40% of postmenopausal women age 50–74 in the United States had used HT. This widespread use occurred despite the paucity of conclusive data, until recently, on the health consequences of such therapy. Although many women rely on their health care providers for a definitive answer to the question of whether to use postmenopausal hormones, balancing the benefits and risks for an individual patient is challenging.
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Although observational studies suggest that HT prevents cardiovascular and other chronic diseases, the apparent benefits may result at least in part from differences between women who opt to take postmenopausal hormones and women who do not. Those choosing HT tend to be healthier, have greater access to medical care, are more compliant with prescribed treatments, and maintain a more health-promoting lifestyle. Randomized trials, which eliminate these confounding factors, have not consistently confirmed the benefits found in observational studies. Indeed, the largest HT trial to date, the Women’s Health Initiative (WHI), which examined more than 27,000 postmenopausal women age 50–79 (mean age, 63) for an average of 5–7 years, was stopped early because of an overall unfavorable benefit-risk ratio in the estrogen-progestin arm and an excess risk of stroke that was not offset by a reduced risk of coronary heart disease (CHD) in the estrogen-only arm.
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The following summary offers a decision-making guide based on a synthesis of currently available evidence. Prevention of cardiovascular disease is eliminated from the equation due to lack of evidence for such benefits in recent randomized clinical trials.
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BENEFITS AND RISKS OF POSTMENOPAUSAL HORMONE THERAPY
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Symptoms of menopause
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Compelling evidence, including data from randomized clinical trials, indicates that estrogen therapy is highly effective for controlling vasomotor and genitourinary symptoms. Alternative approaches, including the use of antidepressants (such as paroxetine, 7.5 mg/d; or venlafaxine, 75–150 mg/d), gabapentin (300–900 mg/d), clonidine (0.1–0.2 mg/d), or vitamin E (400–800 IU/d), or the consumption of soy-based products or other phytoestrogens, may also alleviate vasomotor symptoms, although they are less effective than HT. Paroxetine is the only nonhormonal drug approved by the U.S. Food and Drug Administration for treatment of vasomotor symptoms. Bazedoxifene, an estrogen agonist/antagonist, in combination with conjugated estrogens has also received approval for vasomotor symptom management. For genitourinary symptoms, the efficacy of vaginal estrogen is similar to that of oral or transdermal estrogen; oral ospemifene is an additional option.
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By reducing bone turnover and resorption rates, estrogen slows the aging-related bone loss experienced by most postmenopausal women. More than 50 randomized trials have demonstrated that postmenopausal estrogen therapy, with or without a progestogen, rapidly increases bone mineral density at the spine by 4–6% and at the hip by 2–3% and that those increases are maintained during treatment.
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Data from observational studies indicate a 50–80% lower risk of vertebral fracture and a 25–30% lower risk of hip, wrist, and other peripheral fractures among current estrogen users; addition of a progestogen does not appear to modify this benefit. In the WHI, 5–7 years of either combined estrogen-progestin or estrogen-only therapy was associated with a 33% reduction in hip fractures and 25–30% fewer total fractures among a population unselected for osteoporosis. Bisphosphonates (such as alendronate, 10 mg/d or 70 mg once per week; risedronate, 5 mg/d or 35 mg once per week; or ibandronate, 2.5 mg/d or 150 mg once per month or 3 mg every 3 months IV) and raloxifene (60 mg/d), a selective estrogen receptor modulator (SERM), have been shown in randomized trials to increase bone mass density and decrease fracture rates. Other options for treatment of osteoporosis are bazedoxifene in combination with conjugated estrogens and parathyroid hormone (teriparatide, 20 μg/d SC). These agents, unlike estrogen, do not appear to have adverse effects on the endometrium or breast. Increased physical activity, adequate calcium intake (1000–1200 mg/d through diet or supplements in two or three divided doses), and adequate vitamin D intake (600–1000 IU/d) may also reduce the risk of osteoporosis-related fractures. According to the Institute of Medicine’s 2011 report, 25-hydroxyvitamin D blood levels of ≥50 nmol/L are sufficient for bone-density maintenance and fracture prevention. The Fracture Risk Assessment (FRAX¯) score, an algorithm that combines an individual’s bone-density score with age and other risk factors to predict her 10-year risk of hip and major osteoporotic fracture, may be of use in guiding decisions about pharmacologic treatment (see www.shef.ac.uk/FRAX/).
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Endometrial cancer (with estrogen alone)
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A combined analysis of 30 observational studies found a tripling of endometrial cancer risk among short-term users (1–5 years) of unopposed estrogen and a nearly tenfold increased risk among long-term users (≥10 years). These findings are supported by results from the randomized Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, in which 24% of women assigned to unopposed estrogen for 3 years developed atypical endometrial hyperplasia—a premalignant lesion—as opposed to only 1% of women assigned to placebo. Use of a progestogen, which opposes the effects of estrogen on the endometrium, eliminates these risks and may even reduce risk (see later).
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Venous thromboembolism
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A meta-analysis of observational studies found that current oral estrogen use was associated with a 2.5-fold increase in risk of venous thromboembolism in postmenopausal women. A meta-analysis of randomized trials, including the WHI, found a 2.1-fold increase in risk. Results from the WHI indicate a nearly twofold increase in risk of pulmonary embolism and deep vein thrombosis with estrogen-progestin and a 35–50% increase in these risks with estrogen-only therapy. Transdermal estrogen, taken alone or with certain progestogens (micronized progesterone or pregnane derivatives), appears to be a safer alternative with respect to thrombotic risk.
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Breast cancer (with estrogen-progestin)
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An increased risk of breast cancer has been found among current or recent estrogen users in observational studies; this risk is directly related to duration of use. In a meta-analysis of 51 case-control and cohort studies, short-term use (<5 years) of postmenopausal HT did not appreciably elevate breast cancer incidence, whereas long-term use (≥5 years) was associated with a 35% increase in risk. In contrast to findings for endometrial cancer, combined estrogen-progestin regimens appear to increase breast cancer risk more than estrogen alone. Data from randomized trials also indicate that estrogen-progestin raises breast cancer risk. In the WHI, women assigned to receive combination hormones for an average of 5.6 years were 24% more likely to develop breast cancer than women assigned to placebo, but 7.1 years of estrogen-only therapy did not increase risk. Indeed, the WHI showed a trend toward a reduction in breast cancer risk with estrogen alone, although it is unclear whether this finding would pertain to formulations of estrogen other than conjugated equine estrogens or to treatment durations of >7 years. In the Heart and Estrogen/Progestin Replacement Study (HERS), 4 years of combination therapy was associated with a 27% increase in breast cancer risk. Although the latter finding was not statistically significant, the totality of evidence strongly implicates estrogen-progestin therapy in breast carcinogenesis.
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Some observational data suggest that the length of the interval between menopause onset and HT initiation may influence the association between such therapy and breast cancer risk, with a “gap time” of <3–5 years conferring a higher HT-associated breast cancer risk. (This pattern of findings contrasts with that for CHD, as discussed later in this chapter.) However, this association remains inconclusive and may be a spurious finding attributable to higher rates of screening mammography and thus earlier cancer detection in HT users than in nonusers, especially in early menopause. Indeed, in the WHI trial, hazard ratios for HT and breast cancer risk did not differ among women 50–59, those 60–69, and those 70–79 years of age at trial entry. (There was insufficient power to examine finer age categories.) Additional research is needed to clarify the issue.
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Large observational studies report a two- to threefold increased risk of gallstones or cholecystectomy among postmenopausal women taking oral estrogen. In the WHI, women randomized to estrogen-progestin or estrogen alone were ∼55% more likely to develop gallbladder disease than those assigned to placebo. Risks were also increased in HERS. Transdermal HT might be a safer alternative, but further research is needed.
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Probable or uncertain risks and benefits
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Coronary heart disease/stroke
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Until recently, HT had been enthusiastically recommended as a possible cardioprotective agent. In the past three decades, multiple observational studies suggested, in the aggregate, that estrogen use leads to a 35–50% reduction in CHD incidence among postmenopausal women. The biologic plausibility of such an association is supported by data from randomized trials demonstrating that exogenous estrogen lowers plasma low-density lipoprotein (LDL) cholesterol levels and raises high-density lipoprotein (HDL) cholesterol levels by 10–15%. Administration of estrogen also favorably affects lipoprotein(a) levels, LDL oxidation, endothelial vascular function, fibrinogen, and plasminogen activator inhibitor 1. However, estrogen therapy has unfavorable effects on other biomarkers of cardiovascular risk: it boosts triglyceride levels; promotes coagulation via factor VII, prothrombin fragments 1 and 2, and fibrinopeptide A elevations; and raises levels of the inflammatory marker C-reactive protein.
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Randomized trials of estrogen or combined estrogen-progestin in women with preexisting cardiovascular disease have not confirmed the benefits reported in observational studies. In HERS (a secondary-prevention trial designed to test the efficacy and safety of estrogen-progestin therapy with regard to clinical cardiovascular outcomes), the 4-year incidence of coronary death and nonfatal myocardial infarction was similar in the active-treatment and placebo groups, and a 50% increase in risk of coronary events was noted during the first year among participants assigned to the active-treatment group. Although it is possible that progestin may mitigate estrogen’s benefits, the Estrogen Replacement and Atherosclerosis (ERA) trial indicated that angiographically determined progression of coronary atherosclerosis was unaffected by either opposed or unopposed estrogen treatment. Moreover, no cardiovascular benefit was found in the Papworth Hormone Replacement Therapy Atherosclerosis Study, a trial of transdermal estradiol with and without norethindrone; the Women’s Estrogen for Stroke Trial (WEST), a trial of oral 17β-estradiol; or the Estrogen in the Prevention of Reinfarction Trial (ESPRIT), a trial of oral estradiol valerate. Thus, in clinical trials, HT has not proved effective for the secondary prevention of cardiovascular disease in postmenopausal women.
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Primary-prevention trials also suggest an early increase in cardiovascular risk and an absence of cardioprotection with postmenopausal HT. In the WHI, women assigned to 5.6 years of estrogen-progestin therapy were 18% more likely to develop CHD (defined in primary analyses as nonfatal myocardial infarction or coronary death) than those assigned to placebo, although this risk elevation was not statistically significant. However, during the trial’s first year, there was a significant 80% increase in risk, which diminished in subsequent years (p for trend by time = .03). In the estrogen-only arm of the WHI, no overall effect on CHD was observed during the 7.1 years of the trial or in any specific year of follow-up. This pattern of results was similar to that for the outcome of total myocardial infarction.
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However, a closer look at available data suggests that timing of initiation of HT may critically influence the association between such therapy and CHD. Estrogen may slow early stages of atherosclerosis but have adverse effects on advanced atherosclerotic lesions. It has been hypothesized that the prothrombotic and proinflammatory effects of estrogen manifest themselves predominantly among women with subclinical lesions who initiate HT well after the menopausal transition, whereas women with less arterial damage who start HT early in menopause may derive cardiovascular benefit because they have not yet developed advanced lesions. Nonhuman primate data support this concept. Conjugated estrogens had no effect on the extent of coronary artery plaque in cynomolgus monkeys assigned to receive estrogen alone or combined with progestin starting 2 years (∼6 years in human terms) after oophorectomy and well after the establishment of atherosclerosis. However, administration of exogenous hormones immediately after oophorectomy, during the early stages of atherosclerosis, reduced the extent of plaque by 70%.
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Lending further credence to this hypothesis are results of subgroup analyses of observational and clinical trial data. For example, among women who entered the WHI trial with a relatively favorable cholesterol profile, estrogen with or without progestin led to a 40% lower risk of incident CHD. Among women who entered with a worse cholesterol profile, therapy resulted in a 73% higher risk (p for interaction = .02). The presence or absence of the metabolic syndrome (Chap. 22) also strongly influenced the relation between HT and incident CHD. Among women with the metabolic syndrome, HT more than doubled CHD risk, whereas no association was observed among women without the syndrome. Moreover, although there was no association between estrogen-only therapy and CHD in the WHI trial cohort as a whole, such therapy was associated with a CHD risk reduction of 40% among participants age 50–59; in contrast, a risk reduction of only 5% was observed among those age 60–69, and a risk increase of 9% was found among those age 70–79 (p for trend by age = .08). For the outcome of total myocardial infarction, estrogen alone was associated with a borderline-significant 45% reduction and a nonsignificant 24% increase in risk among the youngest and oldest women, respectively (p for trend by age = .02). Estrogen was also associated with lower levels of coronary artery calcified plaque in the younger age group. Although age did not have a similar effect in the estrogen-progestin arm of the WHI, CHD risks increased with years since menopause (p for trend = .08), with a significantly elevated risk among women who were ≥20 years past menopause. For the outcome of total myocardial infarction, estrogen-progestin was associated with a 9% risk reduction among women <10 years past menopause as opposed to a 16% increase in risk among women 10–19 years past menopause and a twofold increase in risk among women >20 years past menopause (p for trend = .01). In the large observational Nurses’ Health Study, women who chose to start HT within 4 years of menopause experienced a lower risk of CHD than did nonusers, whereas those who began therapy ≥10 years after menopause appeared to receive little coronary benefit. Observational studies include a high proportion of women who begin HT within 3–4 years of menopause, whereas clinical trials include a high proportion of women ≥12 years past menopause; this difference helps to reconcile some of the apparent discrepancies between the two types of studies.
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For the outcome of stroke, WHI participants assigned to estrogen-progestin or estrogen alone were ∼35% more likely to suffer a stroke than those assigned to placebo. Whether or not age at initiation of HT influences stroke risk is not well understood. In the WHI and the Nurses’ Health Study, HT was associated with an excess risk of stroke in all age groups. Further research is needed on age, time since menopause, and other individual characteristics (including biomarkers) that predict increases or decreases in cardiovascular risk associated with exogenous HT. Furthermore, it remains uncertain whether different doses, formulations, or routes of administration of HT will produce different cardiovascular effects.
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Observational studies have suggested that HT reduces risks of colon and rectal cancer, although the estimated magnitudes of the relative benefits have ranged from 8% to 34% in various meta-analyses. In the WHI (the sole trial to examine the issue), estrogen-progestin was associated with a significant 38% reduction in colorectal cancer over a 5.6-year period, although no benefit was seen with 7 years of estrogen-only therapy. However, a modifying effect of age was observed, with a doubling of risk with HT in women age 70–79 but no risk elevation in younger women (p for trend by age = .02).
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Cognitive decline and dementia
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A meta-analysis of 10 case-control and two cohort studies suggested that postmenopausal HT is associated with a 34% decreased risk of dementia. Subsequent randomized trials (including the WHI), however, have failed to demonstrate any benefit of estrogen or estrogen-progestin therapy on the progression of mild to moderate Alzheimer’s disease and/or have indicated a potential adverse effect of HT on the incidence of dementia, at least in women ≥65 years of age. Among women randomized to HT (as opposed to placebo) at age 50–55 in the WHI, no effect on cognition was observed during the postintervention phase. Determining whether timing of initiation of HT influences cognitive outcomes will require further study.
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Ovarian cancer and other disorders
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On the basis of limited observational and randomized data, it has been hypothesized that HT increases the risk of ovarian cancer and reduces the risk of type 2 diabetes mellitus. Results from the WHI support these hypotheses. The WHI also found that HT use was associated with an increased risk of urinary incontinence and that estrogen-progestin was associated with increased rates of lung cancer mortality.
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Endometrial cancer (with estrogen-progestin)
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In the WHI, use of estrogen-progestin was associated with a nonsignificant 17% reduction in risk of endometrial cancer. A significant reduction in risk emerged during the postintervention period (see later).
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In the overall WHI cohort, estrogen with or without progestin was not associated with all-cause mortality. However, there was a trend toward reduced mortality in younger women, particularly with estrogen alone. For women 50–59, 60–69, and 70–79 years of age, relative risks (RRs) associated with estrogen-only therapy were 0.70, 1.01, and 1.21, respectively (p for trend = .04).
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Overall benefit-risk profile
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Estrogen-progestin was associated with an unfavorable benefit-risk profile (excluding relief from menopausal symptoms) as measured by a “global index”—a composite outcome including CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer, hip fracture, and death (Table 16-1)—in the WHI cohort as a whole, and this association did not vary by 10-year age group. Estrogen-only therapy was associated with a neutral benefit-risk profile in the WHI cohort as a whole. However, there was a significant trend toward a more favorable benefit-risk profile among younger women and a less favorable profile among older women, with RRs of 0.84, 0.99, and 1.17 for women 50–59, 60–69, and 70–79 years of age, respectively (p for trend by age = .02).
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Changes in health status after discontinuation of hormone therapy
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In the WHI, many but not all risks and benefits associated with active use of HT dissipated within 5–7 years after discontinuation of therapy. For estrogen-progestin, an elevated risk of breast cancer persisted (RR = 1.28 [95% confidence interval, 1.11–1.48]) during a cumulative 12-year follow-up period (5.6 years of treatment plus 6.8 years of postintervention observation), but most cardiovascular disease risks became neutral. A reduction in hip fracture risk persisted (RR = 0.81 [0.68–0.97]), and a significant reduction in endometrial cancer risk emerged (RR = 0.67 [0.49–0.91]). For estrogen alone, the reduction in breast cancer risk became statistically significant (RR = 0.79 [0.65–0.97]) during a cumulative 12-year follow-up period (6.8 years of treatment plus 5.1 years of postintervention observation), and significant differences by age group persisted for total myocardial infarction and the global index, with more favorable results for younger women.
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APPROACH TO THE PATIENT: Postmenopausal Hormone Therapy
The rational use of postmenopausal HT requires balancing the potential benefits and risks. Figure 16-3 provides one approach to decision making. The clinician should first determine whether the patient has moderate to severe menopausal symptoms—the primary indication for initiation of systemic HT. Systemic HT may also be used to prevent osteoporosis in women at high risk of fracture who cannot tolerate alternative osteoporosis therapies. (Vaginal estrogen or other medications may be used to treat urogenital symptoms in the absence of vasomotor symptoms.) The benefits and risks of such therapy should be reviewed with the patient, giving more emphasis to absolute than to relative measures of effect and pointing out uncertainties in clinical knowledge where relevant. Because chronic disease rates generally increase with age, absolute risks tend to be greater in older women, even when relative risks remain similar. Potential side effects—especially vaginal bleeding that may result from use of the combined estrogen-progestogen formulations recommended for women with an intact uterus—should be noted. The patient’s own preference regarding therapy should be elicited and factored into the decision. Contraindications to HT should be assessed routinely and include unexplained vaginal bleeding, active liver disease, venous thromboembolism, history of endometrial cancer (except stage 1 without deep invasion) or breast cancer, and history of CHD, stroke, transient ischemic attack, or diabetes. Relative contraindications include hypertriglyceridemia (>400 mg/dL) and active gallbladder disease; in such cases, transdermal estrogen may be an option. Primary prevention of heart disease should not be viewed as an expected benefit of HT, and an increase in the risk of stroke as well as a small early increase in the risk of coronary artery disease should be considered. Nevertheless, such therapy may be appropriate if the noncoronary benefits of treatment clearly outweigh the risks. A woman who suffers an acute coronary event or stroke while taking HT should discontinue therapy immediately.
Short-term use (<5 years for estrogen-progestogen and <7 years for estrogen alone) is appropriate for relief of menopausal symptoms among women without contraindications to such use. However, such therapy should be avoided by women with an elevated baseline risk of future cardiovascular events. Women who have contraindications for or are opposed to HT may derive benefit from the use of certain antidepressants (including venlafaxine, fluoxetine, or paroxetine), gabapentin, clonidine, soy, or black cohosh and, for genitourinary symptoms, intravaginal estrogen creams or devices, or ospemifene.
Long-term use (≥5 years for estrogen-progestogen and ≥7 years for estrogen alone) is more problematic because a heightened risk of breast cancer must be factored into the decision, especially for estrogen-progestogen. Reasonable candidates for such use include the small percentage of postmenopausal women who have persistent severe vasomotor symptoms along with an increased risk of osteoporosis (e.g., those with osteopenia, a personal or family history of nontraumatic fracture, or a weight below 125 lbs), who also have no personal or family history of breast cancer in a first-degree relative or other contraindications, and who have a strong personal preference for therapy. Poor candidates are women with elevated cardiovascular risk, those at increased risk of breast cancer (e.g., women who have a first-degree relative with breast cancer, susceptibility genes such as BRCA1 or BRCA2, or a personal history of cellular atypia detected by breast biopsy), and those at low risk of osteoporosis. Even for reasonable candidates, strategies to minimize dose and duration of use should be employed. For example, women using HT to relieve intense vasomotor symptoms in early postmenopause should consider discontinuing therapy within 5 years, resuming it only if such symptoms persist. Because of the role of progestogens in increasing breast cancer risk, regimens that employ cyclic rather than continuous progestogen exposure as well as formulations other than medroxyprogesterone acetate should be considered if treatment is extended. For prevention of osteoporosis, alternative therapies such as bisphosphonates or SERMs should be considered. Research on alternative progestogens and androgen-containing preparations has been limited, particularly with respect to long-term safety. Additional research on the effects of these agents on cardiovascular disease, glucose tolerance, and breast cancer will be of particular interest.
In addition to HT, lifestyle choices such as smoking abstention, adequate physical activity, and a healthy diet can play a role in controlling symptoms and preventing chronic disease. An expanding array of pharmacologic options (e.g., bisphosphonates, SERMs, and other agents for osteoporosis; cholesterol-lowering or antihypertensive agents for cardiovascular disease) should also reduce the widespread reliance on hormone use. However, short-term HT may still benefit some women.
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