Benefits and Risks of HT
Confusion can arise among healthcare providers, the lay public, and the media when general concepts of risk are discussed. Understanding HT risks in particular is critical to clinical decision making around menopause and beyond. Because these issues are crucial to a discussion of the role of HT in an individual woman, a special addendum to the 2008 paper was added in this paper to address risk concepts (see Addendum A at http://www.menopause.org/PSHT08.pdf).
Use of HT should be consistent with treatment goals, benefits, and risks for the individual woman. The benefit-risk ratio for an individual woman continually changes with her age and her menopause-related symptoms (eg, vasomotor symptoms, sleep disturbance, vaginal atrophy, dyspareunia, or diminished libido), any of which may have an adverse impact on quality of life (QOL). Risk factors are related to: a woman's baseline disease risks, her age, age at menopause, cause of menopause, time since menopause, and prior use of any hormone including type, route of administration, dose, and medical conditions that emerged during treatment.
Potential benefits and risks are described below for the relevant clinical outcomes.
Vasomotor Symptoms
ET, with or without a progestogen, is the most effective treatment for menopause-related vasomotor symptoms (ie, hot flashes and night sweats) and their potential consequences (eg, diminished sleep quality, irritability, and reduced QOL). Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT. Every systemic ET and EPT product has regulatory agency approval for this indication.
Maximizing the benefit and minimizing the risks of HT are addressed later in this paper. For example, using lower dose preparations has been associated with similar benefits in clinical trials and in some observational studies with lower risks.
Vaginal Symptoms
ET is the most effective treatment for moderate to severe symptoms of vulvar and vaginal atrophy (eg, vaginal dryness, dyspareunia, and atrophic vaginitis). Many systemic ET and EPT products and all local vaginal ET products have regulatory agency approval for treating these vaginal symptoms. Lower doses than previously used, and less frequent administration, often yield satisfactory results. Some systemic ultralow dose regimens may be inadequate for relief of vaginal symptoms. When HT is used for systemic vasomotor symptoms, enquiry about the adequacy of therapy for urogenital atrophy is important. When HT is considered solely for urogenital atrophy, local vaginal ET is generally recommended.
Sexual Function
Relief of moderate to severe vaginal atrophy with systemic or local HT can be effective in relieving dyspareunia, a common cause of intercourse avoidance. Local estrogen may improve coital satisfaction by improving lubrication and increasing blood flow and sensation in vaginal tissues. One oral systemic ET product is approved in the United States for the treatment of pain with intercourse. HT is not recommended as the sole treatment of other problems of sexual function, including diminished libido.
Urinary Health
Local ET may benefit some women with urge incontinence who have vaginal atrophy. Whether ET by any route is effective in treating overactive bladder is unclear. There is controversy as to whether local ET can improve certain cases of pure stress incontinence. On the other hand, systemic HT may worsen or provoke stress incontinence, perhaps related to changes in uterine volume or periurethral collagen.
Local ET may help reduce the risk of recurrent urinary tract infection (UTI) by a direct proliferative effect on the urethra and bladder epithelia, helping to restore the acidic environment and normal lactobacillus-predominant flora of the vagina, and thus discouraging colonization of the vagina by pathogens associated with UTI. Clinically, only ET administered by the vaginal route has been shown in an RCT to be effective in reducing the risk of recurrent UTI. However, no ET/EPT product has regulatory agency approval for any urinary health indication.
Change in Body Weight/Mass
Body mass index (BMI) increases with age in midlife, with the peak BMI occurring between ages 50 and 59. At this time of life, other factors may also contribute to weight gain, including a decrease in energy expenditure and an increase in energy intake coupled with a decrease in metabolic rate. In women, the hormonal changes associated with the menopause transition can affect body composition and add to the tendency to gain weight. No statistically significant difference in mean weight gain or BMI has been demonstrated between women who use HT and those who do not.
Quality of Life
Although no HT product has regulatory agency approval for enhancing QOL, an improvement in health-related quality of life (HQOL) can result with HT use because of decreased menopause symptoms and perhaps other mechanisms, including improved sleep and a possible elevation of mood that leads to a feeling of well-being. Whether HT improves HQOL in asymptomatic women is unknown, nor are data available to determine the effect of HT on global QOL (the sense of well-being with or without symptoms or physical impairments).
Osteoporosis
Bone strength depends on both bone quality and bone mineral density (BMD). Changes in BMD alone may not always reflect fracture risk. There is RCT evidence that HT reduces postmenopausal osteoporotic fractures, including hip fractures, even in women without osteoporosis, although no HT product has regulatory agency approval for treatment of osteoporosis. Many systemic HT products, however, have regulatory agency approval for prevention of postmenopausal osteoporosis through long-term treatment; a current list of these products can be found on the NAMS Web site (http://www.menopause.org/edumaterials/otcharts.pdf).
Extended use of HT is an option for women who have established reduction in bone mass, regardless of menopause symptoms; for prevention of further bone loss and/or reduction of osteoporotic fracture when alternate therapies are not appropriate or cause side effects; or when the benefits of extended use are expected to exceed the risks. The optimal time to initiate HT and the optimal duration of therapy have not been established, but HT would largely be used in the early years after menopause. The benefits of HT on bone mass dissipate quickly after discontinuation of treatment.
Cardiovascular Effects
Three primary cardiovascular effects are discussed: coronary heart disease (CHD), stroke, and venous thromboembolism (VTE).
Coronary Heart Disease Most observational and preclinical studies support the potential benefits of systemic HT in reducing the risk of CHD. Most RCTs do not. However, it is now understood that the characteristics of women participating in observational studies are markedly different from those of women enrolled in RCTs, and that some of these demographic or biologic differences, or both, influence baseline cardiovascular risks and may modify the effects of HT on cardiovascular risk.
Timing of Initiation. Data indicate that the disparity in findings between observational studies and RCTs is related in part to the timing of initiation of HT in relation to age and proximity to menopause. Most women studied in observational studies of CHD risk were younger than age 55 at the time HT was initiated and within 2 to 3 years of menopause. On the other hand, women enrolled to date in RCTs with clinical cardiovascular endpoints were an average of 63 to 64 years old and more than 10 years beyond menopause. When analyzed by age and time since menopause at initiation of HT, the ET arm of the WHI is in general agreement with observational studies indicating that ET may reduce CHD risk (coronary revascularization and composite outcomes) when initiated in younger and more recently postmenopausal women. In a secondary analysis of WHI data, there was a statistically significant reduction in the composite endpoint of myocardial infarction, coronary artery revascularization, and coronary death in women who were randomized to ET during ages 50 to 59. Combined data from both the ET and EPT trials of the WHI show a statistical trend of an HT effect relative to placebo on CHD by time since menopause, indicating that women who initiate HT more than 10 years beyond menopause are at increased risk for CHD, and those women who initiate HT within 10 years of menopause tend to have a lower risk of CHD. However, statistical modeling of the combined WHI data, including further data from WHI observational studies, did not find that CHD risks varied by the timing of HT initiation.
Duration of Therapy. Observational studies suggest that longer duration of HT use is associated with reduced risk of CHD and related mortality. The WHI RCTs and the WHI observational study suggest a pattern of lower risk of CHD among women who used HT for 5 or more years, but this is not conclusive, and should be considered in light of other factors altered by duration of therapy, such as breast cancer.
In contrast, in the short term, HT is associated with an increase in CHD risk among women who are more distant from menopause at the time of HT initiation.
Coronary Artery Calcium. Observational studies show that long-term HT is associated with less accumulation of coronary artery calcium, which is strongly correlated with atheromatous plaque burden and future risk of clinical CHD events. In an ancillary substudy of younger women (<60 y) in the WHI ET trial, after an average of 7 years of treatment, women who had been randomized to ET had lower levels of coronary artery calcium than those randomized to placebo. These findings suggest that ET initiated by recently postmenopausal women may slow the development of calcified atherosclerotic plaque.
Stroke Results of observational studies of the risk of stroke with HT have been inconsistent. Several studies (including the Nurses' Health Study [NHS], the largest prospective study of HT and stroke) indicated an increased risk of ischemic stroke consistent with the findings from the WHI, whereas other studies showed no effect on stroke risk. The WHI EPT and ET trials demonstrated an increased risk of ischemic stroke and no effect on risk of hemorrhagic stroke. In these trials, there were 8 additional strokes per 10,000 women per year of EPT and 11 additional strokes per 10,000 women per year of ET when the entire cohort was analyzed. In recent analyses that combined results from the WHI EPT and ET trials, HT in younger women (ages 50–59) at study entry had no significant effect on risk of stroke (relative risk [RR], 1.13; 95% confidence interval [CI], 0.73–1.76). In the Framingham Heart Study, natural menopause at age 42 or younger was associated with elevated risk of ischemic stroke.
In women randomized in the WHI within 5 years of menopause, there were 3 additional strokes per 10,000 women per year of EPT, which is not statistically significant. The excess risk of stroke in this age group observed in the WHI studies would fall into the "rare" risk category. Stroke risk was not significantly increased in the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Estrogen for Stroke Trial (WEST) secondary prevention trials. The Women's International Study of long Duration Oestrogen after Menopause (WISDOM) RCT found no excess of stroke in EPT users compared with women on placebo in 1 year.
Findings of increased stroke risk are largely driven by effects of HT on ischemic stroke, as neither ET nor EPT seems to affect the risk of hemorrhagic stroke. However, with few women in younger age groups in the WHI trials, the CIs have been wide, which means that there was not significant statistical power to reach a conclusion. In the NHS, among women ages 50 to 59, the RR of stroke for current EPT users tended to be elevated (RR, 1.34; 95% CI, 0.84–2.13) and was significantly increased for current users of ET (RR, 1.58; 95% CI, 1.06–2.37). Lower doses of estrogen (eg, 0.3 mg CE) were not associated with an increased risk in the NHS, although this was based on the relatively few women who were taking lower doses.
No studies indicate that postmenopausal HT is effective for reducing the risk of a recurrent stroke among women with established cardiovascular disease (CVD) or for prevention of a first stroke, and it may increase the rate of first strokes particularly in women initiating HT over age 60. HT cannot be recommended for the primary or secondary prevention of stroke. Although stroke was not increased in the group ages 50 to 59 in the combined analysis of the WHI, it was almost doubled in the ET group less than 10 years since menopause. This apparent contradiction in the data is hard to explain, but may be due to relatively few events and the difficulty in accurately timing onset of menopause in the ET group.
Venous Thromboembolism Data from both observational studies and RCTs demonstrate an increased risk of VTE with oral HT. In the WHI trials, there were 18 additional VTEs per 10,000 women per year of EPT and 7 additional VTEs per 10,000 women per year of ET when the entire cohort was analyzed. VTE risk in RCTs emerges soon after HT initiation (ie, during the first 1–2 y), and the magnitude of the excess risk seems to decrease somewhat over time. In the WHI trials, the absolute excess VTE risk associated with either EPT or ET was lower in women who started HT before age 60 than in older women who initiated HT after age 60. There were 7 additional VTEs per 10,000 women per year of EPT and 4 additional VTEs per 10,000 women per year of ET in women ages 50 to 59 who were randomized to HT. These risks fall into the rare risk category. The baseline risk of VTE also increases relative to BMI. For obese women (BMI >30), the baseline risk was almost threefold greater. At any BMI, the risk of VTE doubled with HT, and returned to baseline soon after HT discontinuation.
Growing evidence suggests that women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use. There are limited observational data suggesting lower risks of VTE with transdermal than with oral ET, but there are no comparative RCT data on this subject. Lower doses of oral ET may also confer less VTE risk than higher doses, but no comparative RCT data are available to confirm this assumption.
Cardiovascular Effects Conclusion HT is currently not recommended as a sole or primary indication for coronary protection in women of any age. Initiation of HT by women ages 50 to 59 years or by those within 10 years of menopause to treat typical menopause symptoms (eg, vasomotor, vaginal) does not seem to increase the risk of CHD events. There is emerging evidence that initiation of ET in early postmenopause may reduce CHD risk.
Diabetes Mellitus
Aging is associated with an increased risk of non-insulin-dependent diabetes mellitus (DM), also known as adult-onset DM or type 2 DM (T2DM). Although no HT product has regulatory agency approval to prevent DM, large RCTs demonstrate that HT reduces the new onset of T2DM. Women who received active treatment in the WHI EPT arm had an annualized incidence of DM requiring treatment of 0.61% versus 0.76% in placebo-treated women. This translates into a statistically significant 21% reduction (hazard ratio [HR], 0.79; 95% CI, 0.67–0.93) in incident-treated DM, or 15 fewer cases per 10,000 women per year of therapy. A similar statistically significant risk reduction was also noted in the HERS trial (HR, 0.65; 95% CI, 0.48–0.89). In the WHI ET trial, there was a 12% reduction (HR, 0.88; 95% CI, 0.77–1.01) in incident DM, or 14 fewer cases per 10,000 women per year of ET. It is presently unclear whether the mechanism for this benefit is through less centripetal weight gain, reduced insulin resistance in women receiving combined EPT, or some other factor. Meta-analysis data suggest that HT is associated with an improvement in insulin resistance in postmenopausal women. There is inadequate evidence to recommend HT as the sole or primary indication for the prevention of DM in peri- or postmenopausal women.
Optimal glucose control is a prime goal of therapy in postmenopausal women who have T2DM. Some data suggest that postmenopausal women with T2DM who use oral ET may require lower doses of medications for glycemic control.
In women with T2DM, measures to reduce CHD risk are probably of greatest concern. If HT is prescribed, the specific agent, dose, regimen, and route of administration may be important. Transdermal ET administration may offer advantages over the oral route. Serum triglyceride levels and thrombotic factors, which are often increased in patients who have DM, are not increased further with transdermal HT. Moreover, adverse alterations in blood pressure in both nonhypertensive and hypertensive women (although viewed as being rare, if not idiosyncratic, reactions) have been reported only with oral therapy.
Endometrial Cancer
Unopposed systemic ET in postmenopausal women with an intact uterus is associated with increased endometrial cancer risk related to the ET dose and duration of use. Standard-dose therapy (0.625 mg/d CE or the equivalent), when used for more than 3 years, is associated with up to a fivefold increased risk of endometrial cancer; if used for 10 years, the risk increases up to tenfold. This increased risk persists for several years after ET discontinuation. To negate this increased risk, adequate concomitant progestogen is recommended for women with an intact uterus when using systemic ET (see Progestogen indication). HT is not recommended in women with a history of endometrial cancer.
Breast Cancer
Estrogen-progestogen Therapy Diagnosis of breast cancer increases with EPT use beyond 3 to 5 years. In the WHI, this increased risk, in absolute terms, was 8 total breast cancers per 10,000 women using EPT for 5 or more years. Studies have not clarified whether the risk differs between continuous and sequential use of progestogen, with observational studies suggesting risk may be greater with continuous use of progestogen. It is also not clear whether there is a class effect from the progestogen or whether the specific agent used influences breast cancer risk. Early data from a large observational trial suggest that EPT with micronized progesterone may not be associated with an increased risk of breast cancer if used for up to 5 years, but these findings should not be overemphasized and require confirmation.
EPT and, to a lesser extent, ET, increase breast cell proliferation, breast pain, and mammographic density, and EPT may impede the diagnostic interpretation of mammograms. Evolving but not conclusive evidence suggests that the increased risk of breast cancer with EPT may be a result of promotion of preexisting cancers that are too small to be diagnosed by imaging studies or clinical examination. Modest trends suggest that the risk of breast cancer dissipates somewhat over the 3 years after cessation of EPT.
In the WHI, the increase in breast cancer risk was limited to those who had used EPT before enrollment because there was no increased risk of breast cancer in women who were EPT-naive (ie, had not previously used HT). A total of 82% of the women in this study (average age at study entry, 63 y) were hormone-naive. As most women initiate EPT shortly after menopause, a reanalysis of the data examined the effect of a "gap time" (duration of time between onset of menopause and start of EPT) on breast cancer risk. Those starting EPT shortly after menopause experienced an increased risk of breast cancer over the next 5 years, whereas those with a gap time of greater than 5 years did not. The French E3N (a prospective cohort study on French women that examined the potential relationship between pre- and postmenopausal breast cancer occurrence) also reported a greater risk of breast cancer in those women with a short as opposed to a long gap time.
Estrogen Therapy Women in the ET arm of the WHI demonstrated no increase in risk of breast cancer after an average of 7.1 years of use, with 6 fewer cases of invasive breast cancer per 10,000 women per year of ET use, which is not statistically significant. The decrease in risk was observed in all three age groups studied (ie, starting ET at 50–59, 60–69, and 70–79 y). However, the risk was statistically significantly reduced in three subgroups upon post hoc analysis: fewer breast cancers with localized disease were diagnosed in the ET group than in the placebo group (HR, 0.69; 95% CI, 0.51–0.95); a similar reduction was found for ductal carcinomas (HR, 0.71; 95% CI, 0.52–0.99); and a larger, significant reduction was observed in a 6-month follow-up when the women were no longer using ET (HR, 0.67; 95% CI, 0.47–0.97). When ET was extended beyond 10 to 15 years in observational studies, breast cancer risk seemed to increase.
After Breast Cancer Controversy surrounds the issue of safety of EPT in survivors of breast cancer. Observational studies suggest that EPT is safe and perhaps even protective against recurrence of breast cancer. However, these data have been questioned because of the potential bias from selection of women at low risk of recurrence using ET. Two concurrent RCTs reported conflicting results, with one reporting no harm and the other a statistically significant 2.4-fold increase in new breast cancer events. These data would indicate that ET use in breast cancer survivors has not been proven to be safe and may be associated with an increased risk of recurrence.
Ovarian Cancer
Cancer of the ovaries causes more deaths than any other cancer of the reproductive system, primarily because it is usually detected in an advanced stage. In the United States, the 1- and 5-year survival rates are 79% and 53%, respectively. If ovarian cancer is detected and treated early, 95% of women survive at least 5 years; however, only 25% of cases are detected at the earliest, localized stage. Ovarian cancer accounts for 4% of all malignancies among US women and is the fifth leading cause of cancer deaths among US and Canadian women.
Published data on the role of HT and risk of ovarian cancer are conflicting. Most epidemiologic studies have shown no association or a modest increase. There is a relatively large volume of observational trial data that points to an association between HT use and increased ovarian cancer risk.
In the WHI (the only RCT to date to study ovarian cancer), postmenopausal women taking daily continuous-combined EPT for an average follow-up of 5.6 years did not exhibit a statistically significant increase in ovarian cancer. There were 20 cases of invasive ovarian cancer among EPT recipients (n = 8,506) and 12 cases among those taking placebo (n = 8,102). This translates to 42 cases per 100,000 for HT users and 27 cases per 100,000 per year for the placebo group.
Case control and cohort epidemiological studies have reported ovarian cancer risks with both ET and EPT. A large population-based study of peri- and postmenopausal Danish women, followed for an average of 8 years, found that current HT users had incidence ratios of 1.38 (95% CI, 1.26–1.51) for all ovarian tumors and 1.44 (95% CI, 1.30–1.58) for epithelial ovarian cancer. A total of 2 to 4 years after HT cessation, risk declined to 0.98 (95% CI, 0.75–1.28). The risk attributable to HT was 0.6 women per 1,000 per 5 years.
One meta-analysis reported an increase in annual ovarian cancer risk for EPT of 1.11-fold (95% CI, 1.02–1.21) and 1.28-fold (95% CI, 1.18–1.40) for ET. A second meta-analysis reported an RR of 1.24 (95% CI, 1.15–1.34) for any HT. Current HT users for less than 5 years had no significant increase in risk (RR, 1.04; 95% CI 0.91–1.20) compared with women who had used HT for more than 5 years (RR, 1.47; 95% CI, 1.12–1.92), with higher risks for ET than for EPT.
The association between ovarian cancer and HT beyond 5 years, if any, would fall into the rare or very rare category. Women at increased risk of ovarian cancer (eg, those with a family history) should be counseled about this rare association.
Lung Cancer
The leading cause of cancer mortality in North American women and men is lung cancer; 87% of the deaths occur in smokers, and lung cancer annually results in twice as many deaths in women as does breast cancer.
In a post-hoc analysis of the EPT arm of the WHI that combined data from 0 to 4 years of follow-up, the incidence of non-small cell lung cancer (which accounts for about 80% of lung cancer) was not significantly increased (HR, 1.23; 95% CI, 0.92–1.63; P = 0.16), but the number of deaths and the number of poorly differentiated and metastatic tumors increased in the treatment group (HR 1.87; 95% CI, 1.22–2.88; P = 0.004). The cases were essentially limited to past and current smokers and to women older than age 60. As the WHI was not designed to assess lung cancer and chest imaging was not part of the study protocol, the findings are preliminary and require validation in further studies.
The overall data, including the WHI analysis, suggest that initiating EPT in older women with a history of smoking may promote the growth of existing lung cancers. However, evidence from the WHI and some case-control and cohort studies of HT in a younger population (
Several, but not all, studies of midlife women suggest that depressive symptoms are no more common after the menopause transition than before, and most midlife women do not experience more depressive symptoms than younger women do. However, the menopause transition itself, as well as early postmenopause, may be times of heightened vulnerability for a subgroup of women. For women without a history of prior depression, several community-based longitudinal studies have observed an increased risk of onset of major or minor depression during perimenopause or early postmenopause compared with premenopause.
For postmenopausal women without clinical depression, evidence is mixed concerning the effects of HT on mood. Several small, short-term trials among middle-aged women suggested that HT improves mood, whereas other trial results showed no change.
Progestogens in EPT may worsen mood in some women, possibly in those with a history of premenstrual syndrome, premenstrual depressive disorder, or clinical depression.
Only a few RCTs have examined the effects of HT in middle-aged or older women who have depression. Two small RCTs support the antidepressant efficacy of short-term ET in depressed perimenopausal women, whereas one RCT failed to demonstrate the antidepressant efficacy of ET in depressed women who were 5 to 10 years postmenopause. It is controversial whether ET might in some circumstances augment antidepressant effects of selective serotonin reuptake inhibitors.
In conclusion, although HT might have a positive effect on mood and behavior, HT is not an antidepressant and should not be considered as such. Evidence is insufficient to support its use for the treatment of depression.
Cognitive Aging and Dementia
The term "cognition" describes the group of mental processes by which knowledge is acquired or used. With advancing age, performance tends to decline on many, but not all, cognitive tests. Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal cognitive aging. Alzheimer's disease (AD) is the most common cause of dementia.
Findings from well-characterized cohorts suggest that natural menopause has little effect on memory performance or other areas of cognitive function.
For postmenopausal women over age 65, findings from several large, well-designed clinical trials indicate that HT does not improve memory or other cognitive abilities. One trial within WHI-the Women's Health Initiative Memory Study (WHIMS)-of women ages 65 to 79 reported an increase in dementia incidence with HT use. The estimate of dementia cases attributed to HT was 12 per 10,000 persons per year of ET use and 23 per 10,000 persons per year of EPT use.
By way of contrast, a number of observational studies have reported associations between HT and reduced risk of developing AD. HT exposure in observational studies is more likely to involve use by younger women closer to the age of menopause than by women eligible for the WHIMS trial. Speculatively, this difference implies an early window during which HT use might reduce AD risk. However, recall bias and the healthy-user bias may account for protective associations in the observational studies. No clinical trial data address long-term cognitive consequences of HT exposure during the menopause transition and early postmenopause. For women with AD, limited clinical results suggest that ET has no substantial effect on dementia symptoms or progression.
Based on these considerations, HT cannot be recommended at any age for the sole or primary indication of preventing cognitive aging or dementia. HT seems to increase the incidence of dementia when initiated in women age 65 and older. Similarly, HT should not be used to enhance cognitive function in younger postmenopausal women with intact ovaries, although very small clinical trials support the use of ET initiated immediately after menopause induced by bilateral oophorectomy. Available data do not adequately address whether HT used soon after menopause increases or decreases later dementia risk. Limited data do not support the use of HT as treatment of AD.
Premature Menopause and Premature Ovarian Insufficiency
Women experiencing premature menopause (≤40 y) or premature ovarian insufficiency are medically a distinctly different group than women who reach menopause at the median age of 51.3 years. Premature menopause and premature ovarian insufficiency are associated with a lower risk of breast cancer and earlier onset of osteoporosis, CHD, Parkinson's disease; premature bilateral oophorectomy is possibly associated with cognitive decline as well. There are inadequate data regarding HT in these populations. Most observational reports suggest an increased risk of CHD with early natural or surgical menopause in the absence of HT and a protective effect of HT when HT is administered. The existing data regarding HT in women experiencing menopause at the median age should not be extrapolated to women experiencing premature menopause and initiating HT at that time. The risks attributable to HT use by these young women receiving HT may be smaller and the benefits potentially greater than those in older women who commence HT at or beyond the median age of menopause, although no comparative data exist.
Total Mortality
The WHI trials are consistent with observational studies indicating that HT may reduce total mortality when initiated soon after menopause. The WHI suggests that both ET and EPT nonsignificantly reduce total mortality by 30% when initiated in women younger than age 60, and when data from the ET and EPT arms were combined, that reduction with HT use was statistically significant. In contrast, HT was not associated with mortality reduction among women who initiated HT at age 60 or older.
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