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AlzRisk Risk Factor Discussion

Risk Factor:
  (postmenopausal hormone use)
Risk Factor Type: Medications
Current Understanding:
The tables on the Risk Factor Overview present results from a series of observational prospective studies and one randomized controlled trial of postmenopausal hormone therapy (including estrogen alone or in combination with progestin) in relation to AD risk. Overall, in contrast to earlier systematic reviews and meta-analyses, the evidence from these studies does not support benefits on AD risk. The relationship between postmenopausal hormone therapy and AD risk has been controversial; early observational studies, many of them retrospective, suggested a beneficial effect of hormone therapy, and randomized controlled trial results in postmenopausal women suggest that hormone therapy increases dementia risk, and also has adverse effects on other health outcomes. Confounding, as well as differences in the women’s ages, in the timing of use relative to menopause, and in hormone therapy formulation, may account for the disparate findings in earlier observational studies vs. subsequent clinical trials, but more recent observational studies suggest no benefit. Changes over time in the observational findings may be related to changes in hormone therapy use over time. In any case, estrogen remains one of the most effective treatments for relief from menopausal vasomotor symptoms, and, according to the North American Menopause Society, temporary use of hormone therapy may be appropriate to treat low-risk women with severe menopausal symptoms. For a discussion of the putative mechanisms by which hormone therapy may be related to AD risk and commentary on interpreting the findings below in a broader context, please see the Discussion. A longer review and discussion can be found in the closely related published review and meta-analysis, O'Brien J, Jackson JW, Grodstein F, Blacker D, Weuve J. Postmenopausal hormone therapy is not associated with risk of all-cause dementia and Alzheimer's Disease (Epidemiologic Reviews 2014;36:83-103).
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Last Search Completed: 20 March 2014 - (Same date as last content update.)

Risk Factor Overview

O'Brien J, Jackson JW, Weuve J, Blacker D. "Hormone therapy." The AlzRisk Database. Alzheimer Research Forum. Available at: Accessed [date of access]*.

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The tables on the Risk Factor Overview present results from a series of observational prospective studies and one randomized controlled trial of postmenopausal hormone therapy, including estrogen alone or in combination with progestin) in relation to AD risk. In the past, observational studies – mostly retrospective – have suggested a protective effect of hormone therapy on risk of AD. However, over time attitudes about the use of hormone therapy for prevention of age-related diseases have changed, in part because randomized controlled trial results in postmenopausal women suggest that hormone therapy increases dementia risk and also has adverse effects on other health outcomes. Furthermore, evidence supporting a beneficial effect of hormone therapy on AD risk has not emerged in more recent prospective observational studies, nor in our recent meta-analysis that incorporated studies of all-cause dementia, most of which is likely to be AD (O’Brien et al., 2013). Moreover, interpretation of observational data must take into account the influence on medical practice from these trial results, particularly the Heart and Estrogen/Progestin Replacement Study (HERS) (Hulley et al., 1998), published in 1998, and especially the widely publicized Women’s Health Initiative Study (WHI) and associated WHI Memory Study (WHIMS), published in 2003 and 2004 (Shumaker et al., 2003; Shumaker et al., 2004), which led to markedly decreased use of hormone therapy. We review here the methodological context for the observational findings with a focus on possible explanations for differences across time and between observational and clinical trial results.

Please see the related published review and meta-analysis, O'Brien J, Jackson JW, Grodstein F, Blacker D, Weuve J. Postmenopausal hormone therapy is not associated with risk of all-cause dementia and Alzheimer's Disease (Epidemiologic Reviews 2014;36:83-103) for a more detailed discussion of many of the issues discussed here.

Potential Mechanisms of Action

Estrogen, a steroid hormone commonly known for its actions in the reproductive system, also regulates multiple other functions in multiple tissues throughout the body, including brain structures related to memory. There are a number of biological mechanisms through which estrogens might exert neuroprotective effects. These include the promotion of cholinergic activity (Gibbs, 2010), increase in the morphological complexity of neurons associated with learning and memory (e.g., (Brinton et al., 2000), protection from toxic insult (e.g., Brinton et al., 2000), stimulation of neuron formation (e.g., Tanapat et al., 1999), and reduction of the formation of β-amyloid (e.g., Pike et al., 2009), the main constituent of the characteristic amyloid plaques of Alzheimer’s disease.

A large number of in-vitro experiments have demonstrated that estrogen can protect cultured neurons from β-amyloid-related toxicity (Behl et al., 1995; Goodman et al., 1996; Mook-Jung et al., 1997), as well as oxidative stress-related damage (e.g., Behl, 2002). Animal models based on these mechanisms also support potential benefits of estrogen in the CNS. Estrogen is capable of decreasing amyloid accumulation and improving memory performance in ovariectomized rats (Carroll et al., 2007; Shang et al., 2010), and has been shown to enhance long-term potentiation in the hippocampus (a process critical to memory formation) in these rats (Foy et al., 1999). These findings overall suggest that there could be a potential neuroprotective role for estrogen supplementation.

Methodological Issues


Many of the studies included in the tables report on hormone therapy use (versus no use or minimal use), on categories of duration of use, and on broad categories of timing of use (current, former, never). Each of these ways of classifying this exposure has inherent advantages and disadvantages in terms of relevance to AD risk, as discussed below.

The effects of hormone therapy may depend on formulation (especially whether progestin is present), the dosing schedule (i.e., formulas where both estrogen and progestin are taken daily versus formulas that include progestin for only part of the month), the route of administration (e.g., oral, transdermal), and the timing of use in the lifespan (timing relative to menopause, as well as duration of use). Although some studies summarized in the tables report findings specific to some of these factors, few studies captured all of the differences in hormone therapy usage that may have substantial bearing on AD risk, either because the investigators lacked the necessary information, or sample size did not allow for separate or subgroup analyses.

Formulation and Dosing Schedule. During the time the studies were conducted, participants likely took either oral unopposed estrogen (e.g., Premarin) or oral estrogen combined with progestin (e.g., Prempro). Most studies reviewed here either did not provide information about formulation (e.g., (Kawas et al., 1997; Lindsay et al., 2002), or they analyzed opposed and unopposed estrogen therapies together – typically because they had insufficient numbers for separate analyses (e.g., (Tang et al., 1996; Waring et al., 1999; Zandi et al., 2002; Ryan et al., 2009). Studies that did report on formulation were inconsistent; some found higher AD risk for hormone therapy with progestin than for hormone therapy without progestin, although formulation-specific relative risks were not significant (Petitti et al., 2008; Seshadri et al., 20011). A report from the Cache County Study found an inverse association of unopposed estrogen use with AD risk (RR = 0.70, 95% CI: 0.49, 1.01), although this finding was not statistically significant (Shao et al., 2012).

The lack of distinction among these drug/therapy forms may have critical implications for the results. First, for some tissues (e.g., the uterine lining), the presence of progestin prevents some actions of estrogen (Nilsen and Brinton, 2003), and the specific effects on the nervous system are known to differ depending on whether the estrogen preparation includes estrogen alone or a combination of estrogen and progestin (Hogervorst et al., 2009; Henderson and Brinton, 2010). Second, women who take unopposed estrogen may be qualitatively different from those who take a formulation with both estrogen and progestin. In particular, because of the concern about increased uterine cancer risk, unopposed estrogen was more likely to be given to women without a uterus. If opposed and unopposed formulations have different effects on AD risk—or if women who have had hysterectomies differ from those who have not in a way related to AD risk—then it could be unwise to combine different hormone therapy types into one exposure group.

In addition, there are differences among combined estrogen and progestin therapies. In some formulations, both are taken daily (continuous hormone therapy), while others are taken sequentially to better represent the hormone levels of the natural menstrual cycle (i.e., estrogen is taken every day and progestin is added for 10-14 days out of every month). This is one of the differences that may contribute to the dissimilar findings in observational studies vs. clinical trials: the WHIMS trial used a combined hormone therapy formulation with continuous combined therapy, while most women in the observational studies who used combined hormone therapy used sequential preparations (Henderson, 2006). No study has been able to directly compare the effects of sequential versus continuous combined hormone therapy on dementia risk.

Route of Administration. The observational studies reported here rarely discuss the route of administration, but, during the period when most of these studies were conducted, hormone therapy was typically given orally. While this cannot explain differences from the trials, which also primarily studied oral administration, it does affect the ability to generalize any of these results to hormones given by transdermal patch, gels, creams, vaginal rings, and injections, which are in increasingly common use in recent years (Lakey et al., 2010), during a period when overall hormone use is falling. For example, orally-- but not transdermally-- administered estrogen appears to induce hepatic effects such as increased production of C-reactive protein (CRP), an acute-phase reactant, via first-pass metabolism in the liver (Modena et al., 2002) (see the Alzrisk Risk Factor Overview) for an evaluation of the association of CRP with AD risk). Even though the relation of peripheral CRP to AD is unclear, other delivery-based differences in metabolism (Steingold et al., 1991) may also alter any impact of estrogen on AD risk. That said, a 2-year trial of ultra- low-dose transdermal estrogen found no statistically significant difference in cognitive outcomes between those using the patch and those on placebo (Yaffe et al., 2006).

Duration. The duration of hormone therapy use has important implications for the effect of therapy on AD risk. Unfortunately, information is not always available to study exposure duration in detail. Several of the studies reviewed here categorized exposure by duration of use, and some had findings consistent with the notion that AD risk decreases with longer term use (e.g., Tang et al., 1996, Waring et al., 1999, Zandi et al., 2002), but there were very few cases in the longest duration categories. In addition, longer use typically implies earlier initiation, which may be more important, as discussed below. On the risk side, there is evidence that long term use of combined continuous hormone increases the risk of venous thromboembolism, fatal or nonfatal myocardial infarction, stroke, breast cancer, gallbladder disease (Farquhar et al., 2009).

Age of initiation relative to menopause. Most of the reported studies did not distinguish at what age or at what time in their lives relative to menopause women used hormone therapy. However, hormone use in the observational studies was more likely to begin near the time of menopause, when vasomotor symptoms first appear. In some of the first observational studies to analyze perimenopausal use separately, the benefits were generally confined to use during that period. In fact, investigators in the field proposed the “critical window” hypothesis that hormone therapy’s benefit is with use primarily around the menopause. Their reasoning is that estrogen replacement is most beneficial at the time of menopause, when there is a dramatic depletion in estrogen rather just low levels. In contrast, therapy initiated later may accelerate degenerative processes (Mikkola and Clarkson, 2002; Brinton, 2005; Brinton, 2008). For instance, in the Cache County Study (Zandi et al., 2002), when current and former hormone therapy users were analyzed separately, only former hormone therapy use had a protective association with AD risk (hazard ratio: 0.33 [95% CI, 0.15-0.65]). Former users would be expected to include a preponderance of women who initiated therapy at the time menopausal symptoms appeared, while current users would be expected to be more heterogeneous, including those with use beginning at menopause and others beginning more recently. By the same token, another observational study that distinguished hormone therapy use in midlife from late-life found a 26% decreased risk of dementia among women reporting use in midlife, and a 48% increased risk for women reporting only late-life use, in each case comparing to never users (Whitmer et al., 2011). Another study that categorized age of use more finely found AD risk to be lowest in the groups reporting use at the earliest ages [e.g., 50-63] (Henderson et al., 2005).

However, not all prospective studies of hormone therapy and AD risk support the critical window hypothesis. In our recent review and meta-analysis (O’Brien et al., 2013), findings about timing of hormone therapy use and AD risk were inconsistent. Although an updated report from the Cache County Study found significant reductions in AD and all-cause dementia risk with hormone therapy initiation near the time of menopause (Shao et al., 2012), another report found no benefit of starting hormone therapy within 10 years of menopause (Petitti et al., 2008). In one study, risk was actually higher among those who used hormone therapy earlier, although results were not significant (Roberts et al., 2006).

Randomized trials addressing this hypothesis are underway; their design and preliminary findings are described in greater detail below.

Design and Analysis

Sample size and modeling. Many of the studies are fairly large, although because only women can be included, analyses of hormone therapy typically have smaller sample sizes than those of other risk factors, which may limit statistical power. Smaller sample sizes, and, in particular, the smaller case numbers that result, limit the number of covariates that can be included in the analytical models, and therefore, the degree of adjustment for confounding (see Confounding) that is possible. In addition, the wide variety of formulations, broad age range, and other factors described above call for stratified analyses, but sample sizes limit these approaches.

Analyses of time of use variables may be particularly sensitive to modeling issues, given the complex interactions among age of use, life stage of use, duration of use, and current vs. former use, as noted above. In addition, hormone therapy use is not constant through mid to late life but few investigators use time-varying covariates (with or without a lag), whether due to insufficient data, limited sample size, or lack of familiarity with these models.

Confounding. One of the most noted problems in observational studies of hormone therapy is that users differ from non-users in fundamental ways, including being more educated, more affluent, and—at least until the publication of the WHI results—more health conscious. Consistent with this, they tend to have fewer cardiovascular disease risk factors than those who do not take hormone therapy (Matthews, et al., 1996), and to have access to more and better health services. This healthy user bias could explain the protective effects of hormone therapy in many studies, especially those which evaluated hormone therapy use prior to the publication of the WHI results (Grodstein et al., 2003).

Results from Other Lines of Research

Other Observational Studies of AD & Dementia

In our tables, the results from papers reporting on both all-cause dementia and AD were similar (Shao et al., 2012; Ryan et al., 2009; Petitti et al., 2008). One study that reported results for total dementia only (and not on AD, and thus ineligible for inclusion in AlzRisk) found significantly decreased risk with midlife hormone therapy use, significantly increased risk with late-life use, and no association between hormone therapy use and dementia for those with both mid- and late-life use (Whitmer et al., 2011). Another study with dementia-only results found a non-significant increase in dementia risk for any-use of hormone therapy (Ryan et al., 2009b). A plethora of other observational studies on the use of hormone therapy and AD did not meet the inclusion criteria for AlzRisk review. This included a cross-sectional study (Baldereschi et al., 1998), which found a lower prevalence of AD among hormone therapy users, and a large number of case-control studies with variable results (reviewed in Low and Anstey, 2006) that are hard to interpret in light of methodological limitations including small sample size, brief follow-up, recall bias, and differences in ascertainment of cases and controls.

Observational Studies of Cognitive Function

Studies examining cognitive decline as an outcome rather than the development of AD or non-specific dementia have been inconsistent (reviewed in Maki and Hogervorst, 2003; Barrett-Connor and Laughlin, 2009). An observational study of over 16,000 women found no beneficial association between early initiation of hormone therapy and cognitive decline (Kang and Grodstein, 2010). However, a report from the Cache County Study found lifetime hormone therapy exposure to be associated with better cognition and attenuated cognitive decline over a three-year period (Carlson et al., 2001).

Cross-sectional and short-term studies of hormone therapy and cognitive function are also mixed, but there are some positive findings showing an association between hormone therapy and scores in certain cognitive domains (e.g., Low and Anstey, 2006). However, heterogeneity in the domains tested and specific cognitive tests used makes comparisons among studies complex. A review of hormone replacement therapy and cognition was mostly inconclusive, but suggested some benefits on verbal memory, vigilance, reasoning and motor speed for women suffering from menopausal symptoms (LeBlanc et al., 2001).

Randomized Trial of Dementia Outcomes

The large WHIMS randomized trial of hormone therapy with dementia as an outcome (for review of all WHIMS substudies, see Coker et al., 2010) showed no reduction in risk of dementia when conjugated equine estrogens (i.e., estrogen-only therapy) are taken in late life (Shumaker et al., 2004), and an increase in dementia risk with estrogen + progestin supplementation (Shumaker et al., 2003). The differences between results from this randomized trial and many previous observational studies (including many whose design features did not qualify them for inclusion in AlzRisk) have been attributed both to unrecognized bias and critical differences in the biologic questions that these types of studies were addressing, as discussed above. However, our recent meta-analysis of prospective observational studies of all-cause dementia indicated that findings from these studies are not inconsistent with those from WHIMS (O’Brien et al., 2014).

Randomized Trials of Cognitive Function

WHIMS data were extensively analyzed to look at cognitive function outcomes beyond the onset of dementia or AD. Analyses of global cognitive function (see Rapp et al., 2003; Espeland et al., 2004) found harmful effects of estrogen-alone therapy and no benefit of estrogen + progestin use on global cognitive function. In an ancillary trial known as the WHI Study of Cognitive Aging (WHISCA), a subgroup of participants had annual detailed cognitive testing. Analyses of these data also found detrimental associations between of estrogen + progestin use with verbal memory (Resnick et al., 2006), but only after long-term therapy, and other cognitive domains were not affected.

Beyond WHIMS, a meta-analysis of other randomized controlled trials of hormone therapy and cognitive function in postmenopausal, cognitively healthy women found that hormone therapy does not prevent decline in the short or long (up to 5 years) term (Lethaby et al., 2008), and another review concluded that hormone therapy does not provide a clear benefit for maintaining cognitive function in women who already have dementia (Hogervorst et al., 2009). However, these trials may have been too short to pick up the true impact on the trajectory of cognitive change. Furthermore, there is insufficient evidence to determine whether hormone therapy would be beneficial in certain subgroups of women (e.g., younger ages, those with natural v. surgical menopause), or in alternate formulations (e.g., sequential combined therapy) or modes of delivery (e.g., transdermal).

Finally, other trials aim to address some of the remaining questions about timing of hormone therapy initiation. New findings from the Women’s Health Initiative Memory Study of Younger Women (WHIMSY), an expansion of the WHIMS that investigated the effects of hormone therapy in younger postmenopausal women (age 50-55), show neither harm or benefit to cognitive function among those using hormone therapy during this window near the menopause (Espeland et al., 2013). In the Kronos Early Estrogen Prevention Study (KEEPS) (Harman et al., 2005; Wharton et al., 2013), the investigators are assigning recently menopausal women (i.e., within 36 months of their final menstrual period) to hormone therapy. The KEEPS Cognitive and Affective substudy will examine the effect of hormone therapy on standard psychometric tests scores over time. In preliminary reports of the study findings, investigators state that the results for cognitive function are essentially null ( Barker, C., 2013). Another trial – the Early Versus Late Intervention Trial With Estradiol – is examining the effects of oral 17B-estradiol on cognitive decline in healthy post-menopausal women according to years since menopause (either less than 6 years, or 10 years or more). Expected to conclude in 2012-2013, these studies will shed light on the critical window hypothesis and cognitive outcomes.

Trial Results Related to Non-Cognitive Outcomes

The use of hormone therapy for disease prevention overall remains problematic, because randomized controlled trials have demonstrated that hormone therapy increases risk of a variety of adverse health outcomes (e.g., heart disease, breast cancer, stroke, pulmonary embolism, gallbladder disease) (Women’s Health Initiative (WHI) writing group: Rossouw et al., 2002; Anderson et al., 2004). The Heart and Estrogen/Progestin Replacement Study (HERS) (Hulley et al., 1998), a randomized, double-blind, placebo-controlled study in postmenopausal women with established coronary heart disease found no effect of estrogen + progestin therapy on coronary heart disease events. There was an increased risk of venous thromboembolism and non-significant increase in risk of gallbladder disease. There were no differences in risks of other secondary outcomes (breast cancer, endometrial cancer, other cancers and fractures), though the study was not powered for these comparisons.

In an 11-year follow-up analysis of the WHI trial, investigators found that those who took hormone therapy (estrogen combined with progestin) not only had a higher incidence of breast cancer, but the cancers were on average larger and more severe (Chlebowski et al., 2010). Even early initiation of hormone therapy use, which has been hypothesized to have cardiovascular and neurologic benefits, carries an elevated risk of breast cancer (Beral et al., 2011). However, another analysis from the WHI of the women with hysterectomies who took estrogen-only therapy showed that estrogen takers and non takers had no difference in risk of CHD, colon cancer, overall mortality, deep vein thrombosis, stroke, or hip fracture, and takers had a slight reduction in breast cancer risk over the entire follow-up period (LaCroix et al., 2011). A comprehensive overview of the findings from the WHI as well as the extended post-intervention phases does not recommend hormone therapy for disease prevention, given the complex risk-to-benefit ratio of hormone therapy, and the difficulty of interpreting results from subgroup analyses (e.g., age groups) that may have been under powered (Manson, et al., 2013).

Discussion and Recommendations

For many years, estrogen was viewed as a promising treatment for the symptoms of menopause and prevention of age-related diseases in women. The results from earlier observational studies, consistent with this view, suggested that hormone therapy may reduce the risk of AD. However, more recently, additional prospective observational studies and randomized trial results suggest hormone therapy has no benefit or may even increase AD risk, and also contributes to other adverse health outcomes. Differences in the women’s age, in the timing of use relative to menopause, and in hormone therapy formulation may account for the disparate findings, and studies addressing some of these issues are underway. In the meantime, the 2012 North American Menopause Society Position Statement does not recommend the use of hormone therapy for prevention of dementia or other chronic diseases. However, estrogen remains one of the most effective treatments for relief from menopausal vasomotor symptoms, and hormone therapy may be appropriate to treat low-risk individuals with severe menopausal symptoms. Overall, the Menopause Society stresses the importance of considering symptom severity, individual risk profiles, and individual preferences in making decisions about hormone use.


1 The report by Seshadri et al. 2001 was not included in the Alzrisk tables because it did not meet our inclusion criteria. Specifically, we exclude studies lacking systematic diagnostic assessment of all study participants. Cases in this study were identified through medical records only.


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