(postmenopausal hormone use)
Risk Factor Type:
The tables on the Risk Factor Overview present results from a series of observational prospective studies on postmenopausal hormone therapy (including estrogen alone or in combination with progestin) in relation to AD risk. WARNING: Although the findings from these studies, taken collectively, suggest a moderate protective effect of hormone therapy on risk for AD, randomized controlled trial results in postmenopausal women suggest that hormone therapy increases dementia risk, and also has adverse effects on other health outcomes. Thus, any benefits suggested by the observational findings must be weighed carefully against conflicting trial results and other known risks of hormone therapy. 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 observational studies and clinical trials, and studies addressing some of these issues are underway. In the meantime, the 2010 North American Menopause Society Position Statement recommends that hormone therapy should not be used for prevention of dementia or other chronic diseases. However, estrogen remains one of the most effective treatments for relief from menopausal vasomotor symptoms, and the Menopause Society stresses the importance of considering individual risk profiles, since temporary use of hormone therapy may be appropriate to treat low-risk individuals 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.
Last Search Completed:
13 January 2013
O'Brien JO, Weuve J, Blacker D. "Hormone therapy." The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access]*.
* * *
The tables on the Risk Factor Overview present results from a series of observational prospective studies on postmenopausal hormone therapy, including estrogen alone or in combination with progestin) in relation to AD risk. Taken collectively, the findings from these studies suggest a moderate protective effect of hormone therapy on risk of AD. However, this has been a controversial area because randomized controlled trial results in postmenopausal women suggest that hormone therapy increases dementia risk, and also has adverse effects on other health outcomes. Thus, any benefits suggested by the observational findings must be weighed carefully against conflicting trial results and other known risks of hormone therapy. Moreover, interpretation of observational data must take into account the influence on medical practice from these trial results, particularly the widely publicized Women’s Health Initiative Study (WHI) and associated WHI Memory Study (WHIMS), published in 2003 (Shumaker et al., 2003; Shumaker et al., 2004), and the Heart and Estrogen/Progestin Replacement Study (HERS) (Hulley et al., 1998), published in 1998, 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 why they might differ from trial results.
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 (Carrollet 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 a potential neuroprotective role for estrogen supplementation.
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). Only one study reported results for specific formulations of hormone (Seshadri et al., 2001- oral with and without progestin, and transdermal), and found no statistically significant differences in risk of developing AD for all forumations.
The lack of distinction among these forms of drug 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 hormone given by transdermal patch, gels and creams, vaginal rings, and injections, which are in increasingly common use in recent years (Lakey et al. , 2010). 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 http://www.alzrisk.org/riskfactorview.aspx?rfid=7 for an evaluation of the impact of CRP on 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 in mid-life, near the time of menopause, when vasomotor symptoms first appear, and—to the extent that mid-life or perimenopausal use has been analyzed separately—the benefits tended to be confined to use during that period. 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, a recent 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., 2010). 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, it should be noted that one study suggested the opposite effect, and risk was actually higher in those who used earlier (Roberts et al., 2006), though the findings were not significant.
Drawing on the general trend of these findings, investigators in the field have proposed the “critical window” hypothesis that hormone therapy’s benefit is primarily around the menopause. Their reasoning is that estrogen replacement is most beneficial at the 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). Randomized trials addressing this hypothesis are underway, as described below.
Design and Analysis
Sample size and modeling. Although many of the studies are fairly large, analyses of hormone therapy typically have smaller sample sizes than those of other risk factors because only women can be included, 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 the studies reviewed here, all of which evaluated hormone therapy use prior to the publication of the WHI results (e.g., Grodstein et al., 2003).
Results from Other Lines of Research
Other Observational Studies of AD & Dementia
Studies reporting only on total dementia (and not on AD, and thus ineligible for inclusion in AlzRisk) showed no significant impact of hormone therapy on incidence (e.g., Petitti et al., 2008), consistent with findings from studies in the Tables that reported specifically on total dementia (Ryan et al., 2009). 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). A recent 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 improved 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), in contrast to the observational studies, 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 the observational and randomized trial results have been attributed both to unrecognized bias and critical differences in the biologic questions that these types of studies were addressing, as discussed above.
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. Estrogen-alone therapy in WHISCA was associated with lower spatial rotational ability, but did not significantly change any other cognitive domain (Resnick et al., 2009).
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). These trials may have failed to detect effects if they were too short to pick up the true 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).
The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address some of the remaining questions about timing of hormone therapy initiation. 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. 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. (http://clinicaltrials.gov/ct2/show/NCT00154180?id=NCT00154180&rank=1, http://www.keepstudy.org/, http://clinicaltrials.gov/ct2/show/NCT00114517?term=ELITE&id=NCT00114517&rank=1)
Trial Results Related to Non-Cognitive Outcomes
The use of hormone therapy for disease prevention overall remains problematic, since 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 a recently released 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, a recently released 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).
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, 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 in observational studies and clinical trials, and studies addressing some of these issues are underway. In the meantime, the 2010 North American Menopause Society Position Statement recommends that hormone replacement therapy should not be used for prevention of dementia or other chronic diseases. However, estrogen remains one of the most effective treatments for relief from menopausal vasomotor symptoms, and the Menopause Society stresses the importance of considering individual risk profiles, since temporary use of hormone therapy may be appropriate to treat low-risk individuals with severe menopausal symptoms.
1. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
2. Baldereschi M, Di Carlo A, Lepore V, et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging. Neurology. 1998;50(4):996-1002.
3. Barrett-Connor E, Laughlin GA. Endogenous and exogenous estrogen, cognitive function, and dementia in postmenopausal women: evidence from epidemiologic studies and clinical trials. Semin Reprod Med. 2009;27(3):275-282.
4. Behl C. Sex hormones, neuroprotection and cognition. Prog Brain Res. 2002;138:135-142.
5. Behl C, Widmann M, Trapp T, Holsboer F. 17-Beta Estradiol Protects Neurons from Oxidative Stress-Induced Cell Death in Vitro. Biochem Biophys Res Commun. 1995;216(2):473-482.
6. Beral V, Reeves G, Bull D, Green J, Million Women Study Collaborators. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011;103(4):296-305.
7. Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008;31(10):529-537.
8. Brinton RD. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci. 2005;1052:57-74.
9. Brinton RD, Chen S, Montoya M, Hsieh D, Minaya J. The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease. Maturitas. 2000;34 Suppl 2:S35-52.
10. Carlson MC, Zandi PP, Plassman BL, et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology. 2001;57(12):2210-2216.
11. Carroll JC, Rosario ER, Chang L, et al. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007;27(48):13357-13365.
12. Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684-1692.
13. Coker LH, Espeland MA, Rapp SR, et al. Postmenopausal hormone therapy and cognitive outcomes: the Women's Health Initiative Memory Study (WHIMS). J Steroid Biochem Mol Biol. 2010;118(4-5):304-310.
14. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291(24):2959-2968.
15. Farquhar C, Marjoribanks J, Lethaby A, Suckling JA, Lamberts Q. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2009;(2)(2):CD004143.
16. Foy MR, Xu J, Xie X, Brinton RD, Thompson RF, Berger TW. 17beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. J Neurophysiol. 1999;81(2):925-929.
17. Gibbs RB. Estrogen therapy and cognition: a review of the cholinergic hypothesis. Endocr Rev. 2010;31(2):224-253.
18. Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem. 1996;66(5):1836-1844.
19. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med. 2003;348(7):645-650.
20. Henderson VW. The neurology of menopause. Neurologist. 2006;12(3):149-159.
21. Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA, MIRAGE Study Group. Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76(1):103-105.
22. Henderson VW, Brinton RD. Menopause and mitochondria: windows into estrogen effects on Alzheimer's disease risk and therapy. Prog Brain Res. 2010;182:77-96.
23. Hogervorst E, Yaffe K, Richards M, Huppert FA. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev. 2009;(1)(1):CD003799.
24. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605-613.
25. Kang JH, Grodstein F. Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging. 2010.
26. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology. 1997;48(6):1517-1521.
27. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305-1314.
28. Lakey SL, Reed SD, LaCroix AZ, Grothaus L, Newton KM. Self-reported changes in providers' hormone therapy prescribing and counseling practices after the Women's Health Initiative. J Womens Health (Larchmt). 2010;19(12):2175-2181.
29. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001;285(11):1489-1499.
30. Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008;(1)(1):CD003122.
31. Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445-453.
32. Low LF, Anstey KJ. Hormone replacement therapy and cognitive performance in postmenopausal women--a review by cognitive domain. Neurosci Biobehav Rev. 2006;30(1):66-84.
33. Maki P, Hogervorst E. The menopause and HRT. HRT and cognitive decline. Best Pract Res Clin Endocrinol Metab. 2003;17(1):105-122.
34. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol. 1996;143(10):971-978.
35. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res. 2002;53(3):605-619.
36. Modena MG, Bursi F, Fantini G, et al. Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: comparison between oral and transdermal administration of estrogen. Am J Med. 2002;113(4):331-334.
37. Mook-Jung I, Joo I, Sohn S, Kwon HJ, Huh K, Jung MW. Estrogen blocks neurotoxic effects of beta-amyloid (1-42) and induces neurite extension on B103 cells. Neurosci Lett. 1997;235(3):101-104.
38. Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003;100(18):10506-10511.
39. Petitti DB, Crooks VC, Chiu V, Buckwalter JG, Chui HC. Incidence of dementia in long-term hormone users. Am J Epidemiol. 2008;167(6):692-700.
40. Pike CJ, Carroll JC, Rosario ER, Barron AM. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol. 2009;30(2):239-258.
41. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2663-2672.
42. Resnick SM, Espeland MA, An Y, et al. Effects of conjugated equine estrogens on cognition and affect in postmenopausal women with prior hysterectomy. J Clin Endocrinol Metab. 2009;94(11):4152-4161.
43. Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab. 2006;91(5):1802-1810.
44. Roberts RO, Cha RH, Knopman DS, Petersen RC, Rocca WA. Postmenopausal estrogen therapy and Alzheimer disease: overall negative findings. Alzheimer Dis Assoc Disord. 2006;20(3):141-146.
45. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
46. Ryan J, Carriere I, Scali J, et al. Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study. Neurology. 2009;73(21):1729-1737.
47. Seshadri S, Zornberg GL, Derby LE, Myers MW, Jick H, Drachman DA. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch Neurol. 2001;58(3):435-440.
48. Shang XL, Zhao JH, Cao YP, Xue YX. Effects of synaptic plasticity regulated by 17beta-estradiol on learning and memory in rats with Alzheimer's disease. Neurosci Bull. 2010;26(2):133-139.
49. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291(24):2947-2958.
50. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-2662.
51. Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikov S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab. 1991;73(2):275-280.
52. Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci. 1999;19(14):5792-5801.
53. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996;348(9025):429-432.
54. Waring SC, Rocca WA, Petersen RC, O'Brien PC, Tangalos EG, Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology. 1999;52(5):965-970.
55. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: The critical window theory revisited. Ann Neurol. 2010.
56. Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol. 2006;63(7):945-950.
57. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288(17):2123-2129.