PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Front Biosci (Elite Ed). Author manuscript; available in PMC 2013 January 1.
Published in final edited form as:
PMCID: PMC3511049
NIHMSID: NIHMS419855

Sex hormones, aging, and Alzheimer’s disease

Abstract

A promising strategy to delay and perhaps prevent Alzheimer’s disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD.

Keywords: Alzheimer’s disease, Beta-Amyloid, Estrogen, Hormone Therapy, Progesterone, Testosterone, Review

2. INTRODUCTION

Increasing age is the most significant risk factor for the development of Alzheimer’s disease (AD) (13). Even in persons with autosomal dominant mutations and genetic risk factors for AD, the disease develops during middle or advanced ages. Although the factors associated with normal aging that contribute to AD pathogenesis remain to be clearly determined, their identification promises significant insight into the development and perhaps prevention of the disease. In this review, we discuss evidence suggesting that the normal age-related depletion of sex steroid hormones represents an important age-related AD risk factor. The literature indicates that both the relatively abrupt loss of estrogen and progesterone at menopause in women and the more gradual decrease in testosterone in aging men are AD risk factors. As such, therapeutic strategies that counteract age-related depletion of sex steroid hormones may offer significant protection from the development and perhaps treatment of AD.

2.1. Aging and loss of sex hormones

Depletion of sex steroid hormones is an important consequence of normal aging that is associated with vulnerability to disease in hormone-responsive tissues, including the brain (413). Following menopause, women experience relatively rapid loss of the ovarian sex hormones, 17beta-estradiol (E2) and progesterone (P4). Men also experience a significant age-related decrease in circulating testosterone levels, known as androgen deficiency in aging males (ADAM) (4). However, in contrast to menopause, ADAM is not necessarily coupled with the loss of reproductive function and hormonal changes are gradual, with bio-available testosterone levels declining 2–3% annually from approximately 30 years of age (1416). A high level of individual variation is observed in the extent of ADAM (17, 18) and consequently, there is variability in the severity of clinical presentation, which includes reduced muscle and bone mass, increased fat, lethargy, depression and decreased libido (1923).

While age related decline in circulating levels of gonadally produced sex steroid hormones has been well characterized, brain levels of hormones can significantly differ from circulating levels due to sequestration by sex hormone binding globulin, the presence of brain steroid converting enzymes, and neurosteroidogenesis (2427). Few studies have addressed the effects of aging on brain hormone levels. However, female brain levels of E2 have been found to qualitatively mirror circulating E2 levels, with significant declines observed in the brains of postmenopausal women compared to premenopausal women (28), but with very little additional decrease with age after menopause (27, 28). Age-related declines in brain testosterone levels in men have been described, with brain testosterone levels depleted to very low levels by 80 years of age (27, 29). Interestingly, men show reduced but still significant levels of circulating testosterone even at advanced age (5, 16, 30). Further, while circulating levels of the potent androgenic metabolite of testosterone, dihydrotestosterone (DHT), do not appear to change with age (5), age-related declines in brain levels of DHT have been observed in both male rodents (31) and men (27).

2.2. Age-related sex hormone loss and AD risk

If age-related loss of sex steroid hormones is a contributing factor to AD, then it follows that the relatively sudden and extensive loss of E2 and P4 at menopause would result in women having greater vulnerability to AD than men. In fact, like several diseases, AD is characterized by an increased prevalence in women (3238). Although increased lifespan in women complicates the interpretation of sex-differences in AD prevalence, incidence studies also demonstrate that women are at increased risk of AD (3950). Further, more severe cognitive deficits and beta-amyloid (Abeta) neuropathology have been reported in women in comparison to men (5154), although some studies have reported increased tau pathology in men (55, 56).

Sex differences in AD pathology have also been reported in several transgenic mouse models, with increased Abeta accumulation reported in female compared to age-matched male Tg2576 (57, 58), APPswe/PS1 (59, 60) and 3xTgAD transgenic mice (61, 62). Increased vulnerability of the female brain to AD has been primarily attributed to the loss of the neuroprotective sex steroid hormones following menopause, and much evidence from research in animal models and hormone therapy studies supports this notion. However, a recent study provides evidence that the developmental effects of the sex hormones (63) may also influence susceptibility to AD (61). Neonatal male 3xTgAD mice that were demasculinized with the androgen receptor antagonist flutamide exhibited a more female-like pattern of pathology with region-specific increases in Abeta accumulation. Conversely, female 3xTgAD mice defeminized by transient neonatal testosterone treatment showed regional reductions of Abeta accumulation (61). These findings suggest that sex steroid hormones may affect AD risk as a result of both organizational actions during development and loss of activational effects during aging.

Aside from sex differences, comparison of hormone levels demonstrate that age-related depletion of sex steroid hormones is linked with increased risk of AD in both women and men. Multiple studies have described a relationship between AD and low circulating levels of sex steroids - E2 in women and testosterone in men (6471). For example, lower plasma 17beta-estradiol (E2) levels have been observed in women with AD compared to age-matched controls (69). Meanwhile, levels of both total (65, 72) and free plasma testosterone have been observed in men with AD compared to both vascular dementia sufferers (68) and age-matched controls (64, 67, 73, 74). Similarly, assessments of sex steroid hormone levels in the brain have demonstrated depleted testosterone levels observed in male AD brains, and depleted estrone and estradiol in female brain compared to age-matched cognitively normal controls (27, 29, 75, 76). Further, recent evidence suggests synthesis of sex hormones in the brain may also be affected, with altered levels of neurosteroidogenic enzymes observed in AD brains (77, 78).

Importantly, additional evidence suggests that hormone depletion occurs prior to the onset of AD and thus likely contributes to rather than results from the disease process. For example in a longitudinal study of aging men, the relationship between low testosterone and increased risk of AD was present 10 years prior to diagnosis of dementia (73). Further, in comparison to neuropathologically normal men, brain levels of testosterone are significantly lower not only in men with advanced AD but also in men exhibiting mild, AD-related neuropathological changes (29). Interestingly, an emerging literature suggests the possibility that AD pathology may negatively feedback on steroid levels by inhibiting neurosteroidogenesis. Although the regulation of endogenous brain steroid hormone production is incompletely understood, impaired neurosteroidogenesis has been observed in cell lines treated with Abeta and oxidative stress (79, 80), suggesting that depleted brain levels of the sex hormones may promote susceptibility to AD pathogenesis, which in turn could further reduce brain levels of neuroprotective sex hormones.

In AD, not only are brain levels of the sex hormones altered, but brain responsiveness may also be impaired as a result of altered sex hormone receptor levels and distribution. Increased immunoreactivity of the estrogen receptors (ER) ERalpha (81) and ERbeta has been observed in the hippocampus of AD brains (82) and altered cellular localization of ER may also be associated with AD in the hippocampus (83) and hypothalamus (84). Polymorphisms of ERalpha have been linked to both familial and late-onset AD in multiple studies (8592) and recently, reduced alternate splicing of ERalpha has been reported female AD brains (93). Although alternations in expression and distribution of AR in AD are comparatively unexplored, a polymorphism of the androgen receptor has also been associated with AD in men (94).

3. SEX HORMONES REDUCE BETA-AMYLOID LEVELS

If, as available evidence suggests, age-related loss of sex hormones increases the risk of AD, then a critical question is what hormone action(s) are most important to AD pathogenesis. Both estrogens and androgens exert numerous beneficial and protective actions in brain that have potential relevance to AD (Figure 1). As reviewed elsewhere, estrogens and androgens increase spine density and facilitate synaptic plasticity (9599) and improve select aspects of cognition (45, 100107). Also, estrogens and androgens are potent regulators of neuron viability, protecting neurons against a range of toxic insults including those implicated in AD (108112).

Figure 1
Interactions between age-related loss of sex hormones and risk of Alzheimer’s disease. AD pathogenesis is a multifactorial process. Lifetime exposure to a combination of identified genetic and environmental risk factors interacts with numerous ...

Particularly relevant to a protective role against AD, sex hormones are implicated in reducing levels of Abeta, the protein widely implicated as the key initiator of AD pathogenesis. Human studies have associated depleted levels of E2 and testosterone with elevations in neural and plasma Abeta levels. For example, elevated Abeta levels are observed in the cerebrospinal fluid of women with low E2 (113). Further, a preliminary study in postmenopausal women with AD reported that estrogen-based hormone therapy (HT) was associated with lower plasma Abeta40 levels (114). In men, depleted circulating testosterone levels are associated with elevated Abeta levels in both cognitively normal (115, 116) and memory-impaired men (117). Testosterone depletion induced via chemical castration resulted in a corresponding increase in plasma Abeta levels in prostate cancer patients (115, 116). Testosterone levels have also been found to negatively correlate with soluble Abeta levels in brains from aged men (27, 29).

In animal studies, manipulation of E2 and testosterone through gonadectomy and hormone supplementation has also been found to significantly affect Abeta accumulation. Estrogen depletion resulting from ovariectomy (OVX) increases brain Abeta levels in many wild-type rodents and transgenic models of AD, including guinea pigs (118), APP (Tg2575) (119), APPswe (120), CRND8 (121), APP/PS1 (119, 122), and 3xTg-AD mice (123, 124), an effect that is partially reversed with E2 supplementation. However, in some animal models, OVX and E2 treatments do not significantly alter Abeta levels (76, 125129). These discrepancies may reflect experimental differences in timing and dosing of hormone manipulations, or differences in Abeta quantification techniques, since different techniques preferentially detect different pools of Abeta (e.g. soluble vs. insoluble). Strain differences in brain levels of the sex hormones (130) may also contribute to the discrepancies in the effect of OVX on Abeta levels, since in some animal models OVX may be insufficient to induce brain E2 deficiency (76).

Compared to experimental studies in female animals, the effects of castration and testosterone supplementation on Abeta levels in male animals have been more consistent. Castration results in nearly complete loss of endogenous testosterone and corresponding elevations in Abeta in guinea pigs (131), rats (132), and 3xTg-AD mice (133). Because testosterone is a prohormone that is enzymatically converted within tissues to both the active androgen dihydrotestosterone (DHT) and the estrogen E2, there may be contributions from estrogens and androgens to Abeta regulation. In male rats, elevated levels of Abeta induced by castration were prevented by supplementation with DHT but not E2, suggesting a prominent role of androgen pathways (132). Similarly, preventing testosterone conversion to E2 by genetically limiting aromatase activity resulted in elevated testosterone levels, low E2 levels, and reduced Abeta accumulation in male APP23 mice (134). However, in castrated male 3xTg-AD mice, Abeta burden was reduced not only by testosterone and DHT, but also by E2, suggesting that both androgens and estrogens can reduce Abeta in male brain (135).

3.1. Sex hormones regulate beta-amyloid production

The mechanisms by which estrogens and androgens regulate Abeta have yet to be fully elucidated, although both types of sex hormones have been implicated in regulating the production and clearance of Abeta. Production of Abeta results from the proteolytic cleavage of its parent protein, the amyloid precursor protein (APP). The majority of APP is metabolized by two competing pathways, the amyloidogenic and non-amyloidogenic pathways. In the amyloidogenic pathway, APP is sequentially cleaved by beta-secretase (BACE) and gamma-secretase, liberating Abeta peptides that largely occur in two species that are 40 and 42 amino acids in length. In the non-amyloidogenic pathway, APP is cleaved within the Abeta domain by alpha-secretase, preventing formation of full-length Abeta peptide, but releasing a soluble, protective form of APP termed APPalpha (136, 137).

Cell culture studies indicate that both E2 and testosterone may promote APP processing by the non-amyloidogenic route, thereby reducing Abeta production. E2 was first demonstrated to increase secretion of the neurotrophic APPalpha while decreasing Abeta production in non-neuronal cultures (138) and has since been demonstrated in neuronal cell lines and primary neuronal cultures (139141). The role of E2 in non-amyloidogenic APP processing is more difficult to address in vivo. While increased APPalpha levels have been reported in APPswe and CRND8 mice following E2 treatment (120, 121), no effect of OVX and E2 replacement was observed on APPalpha levels in guinea pigs and APP/PS1 mice, despite altered Abeta levels (118, 119). Studies in neuronal/astrocyte co-cultures indicate that astrocytes may interfere with E2 mediated regulation of APPalpha (142), providing an additional layer of complexity to the role of E2 in Abeta production.

Estrogen reduction of Abeta levels via regulation of APP processing may occur by an ER-independent mechanism. For example, ER antagonists do not block E2 mediated increases in APPalpha formation (143). Similar effects are observed in cell lines lacking functional ER (140). The pathway by which E2 may promotes non-amyloidogenic APP processing appears to involve mitogen activated protein kinase (MAPK) signaling including activation of extracellular-regulated kinases 1 & 2 (ERK1/2) (140). Similarly, testosterone has been reported to promote non-amyloidogenic APP processing through the ERK1/2 signaling pathways in cell culture models, increasing APPalpha secretion and decreasing Abeta (144, 145). However, these effects may be the result of the conversion of testosterone to E2 since pharmacological inhibition of aromatase blocks this effect (144, 145). Some evidence also suggests E2 may act through the protein kinase C (PKC) signaling pathway since pharmacological inhibition of PKC attenuates E2-mediated up-regulation of APPalpha formation (140, 146, 147).

In addition to promoting APP processing by the described non-amyloidogenic pathways, sex hormones can affect other aspects of APP metabolism that result in reduced Abeta production. For instance, E2 may actively inhibit pro-amyloidogenic APP proteolysis. Yue and colleagues reported that female APP23 mice made E2 deficient by crossing with aromatase knockout mice resulted in elevated BACE activity and corresponding increases in Abeta (76), suggesting E2 reduces Abeta by inhibiting BACE expression. This idea is reinforced by findings in the CRND8 transgenic mouse model of AD, in which E2 supplementation resulted in decreases in BACE levels, the APP fragments produced from BACE cleavage, and Abeta plaque burden (121). Recent observations in male APP23 mice crossed with aromatase knockout suggest that androgens also down regulate BACE expression and do so in a manner independent of E2 (134). Another potential mechanism by which hormones may reduce Abeta production is limiting APP substrate availability. In female animals, E2 has been shown to affect APP alternate splicing (148) and inhibit APP over-expression following ischemic injury (149). Yet, animal studies that have examined APP levels following E2 manipulation report unaltered levels (119121). It is possible that E2 may alter APP availability for amyloidogenic metabolism without affecting total APP levels through the modulation of APP trafficking. Consistent with this possibility, E2 has been found to reduce APP trafficking to the trans-golgi network, which is the major site for amyloidogenic APP proteolysis, thereby decreasing the substrate pool for Abeta generation (150).

3.2. Sex hormones regulate beta-amyloid clearance

In addition to regulating pathways involved in Abeta production, sex hormones also reduce Abeta levels by modulating mechanisms on Abeta clearance. For example, E2 has been implicated in the clearance of Abeta through stimulation of microglial phagocytosis. In primary cultures of human microglia, E2 stimulated Abeta phagocytosis (151), while microglial cultures from E2 deficient aromatase knockout mice exhibited impaired Abeta clearance (76).

A particularly important mechanism of Abeta in clearance is the degradation of Abeta peptide monomers and oligomers by a variety of proteins collectively referred to as Abeta degrading enzymes (152). Several proteolytic enzymes in which Abeta is a suitable substrate have been identified, including neprilysin, insulin degrading enzyme, transthyretin, endothelin converting enzyme and angiotensin converting enzyme. Analysis of human control and AD cases suggests that neprilysin may be particularly important in regulating pathological accumulation of Abeta (153).

Recent findings demonstrate that both estrogens and androgens significantly increase the expression and/or activity of several Abeta degrading enzymes. In various cell culture and animal model paradigms, E2 has been linked with the regulation of transthyretin (121, 154, 155), insulin degrading enzyme (IDE) (156), and neprilysin (157). For example, E2 increases transthyretin mRNA and protein levels in cultured epithelial cells of the choroid plexus, one of the primary sites of transthyretin synthesis (155). Further, in vivo, E2 administration increased transthyretin in the choroid plexus of OVX rats (155). In cultured rat hippocampal neurons, E2 was found to increase the expression of IDE, while in vivo, OVX was found to decrease hippocampal IDE levels, an effect that was reversed with E2 administration (156). In the same study, E2 treatment was found to promote hippocampal IDE expression while decreasing Abeta accumulation in 12 month-old 3xTgAD mice (156). In a separate study, decreased Abeta and increased cortical transthyretin and IDE levels were observed following E2 administration to CRND8 mice (121). In rats, OVX-induced E2 depletion has also been found to reduce neprilysin activity in total brain homogenate, an effect that was reversed following E2 replacement (157).

Like E2, androgens are also endogenous regulators of Abeta degrading enzymes. Although testosterone does not appear to affect expression of insulin degrading enzyme, it strongly up regulates neuronal expression of neprilysin (160). Consistent with this observation, the neprilysin gene contains at least two androgen response domains, an androgen response region (ARR) and an androgen response element (ARE) (158, 159). Androgens predominantly act through the ARE, while E2 is believed to interact via the ARR (159). Neprilysin expression and activity is modulated by androgens through a classic genomic AR-dependent mechanism, since androgen-dependent regulation of neprilysin is only observed in cultures expressing functional AR and can be inhibited with AR antagonists (160). In animals, increased Abeta and decreased neprilysin levels were observed in male rats following castration, an effect that was reversed with DHT replacement (160). Similar increases in neprilysin and associated decreases in Abeta were recently observed in male APP23 mice crossed with aromatase knockout, a genetic manipulation that increases endogenous levels of testosterone (134). Together, these findings identify sex hormones as significant regulators of Abeta degrading enzymes, a function potentially relevant AD pathogenesis and thus a promising target for therapeutic intervention (Figure 1).

4. PROGESTERONE: THE OTHER SEX HORMONE

In addition to estrogens and androgens, progesterone is increasingly considered for its potential to directly and indirectly regulate AD risk. A progestogen component is typically included in estrogen-based HT for postmenopausal women to counteract oncogenic effects of estrogens on uterus (161164). Although less well studied in the context of AD than estrogens and androgens, progestogens may exert a range of beneficial neural actions relevant to AD (165, 166). Interestingly, both natural progesterone (P4) and synthetic progestins (e.g., medroxyprogesterone acetate) can modulate neuroprotective effects of E2, alternately negating or improving estrogen effects depending upon treatment conditions. As suggested by the cyclic nature of ovarian sex steroid hormone production, key variables in the interactions between estrogens and progestogens may include the timing and duration of hormone exposure.

In behavioral paradigms, P4 interacts with E2, often attenuating the effects of E2. Administration of E2 combined with P4 to young-adult rats was found to worsen OVX-induced impairment in the Morris water maze task, while administration of either E2 or P4 alone did not alter performance (167). In middle-aged OVX rats, progesterone reversed the beneficial effects of both tonic and cyclic E2 administration on spatial reference memory (168). In a conditioned avoidance task, E2 was found to impair performance in OVX rats, while P4 blocked E2-mediated impairment (169). Interestingly, while P4 alone did not affect conditioned avoidance performance following OVX or during diestrus (when E2 levels are low), P4 altered performance at estrus when E2 levels are elevated, suggesting that the behavioral effects of P4 were the result of interactions with E2 (169). Yet P4 does not antagonize E2-mediated cognitive benefits in all experimental paradigms, E2 combined with P4 improved spatial memory performance in aged-OVX rats equally well as E2 alone (170). Detrimental cognitive effects of combined estrogen/progestrogen HT have also been observed in humans. While estrogen alone did not affect cognition in older postmenopausal women, the combination of estrogens and a progestogen was observed to impair cognition (171).

P4 can also modulate the neuroprotective effects of E2 in experimental models of neural injury. In both young-adult and middle-aged OVX rats, P4 blocked E2-mediated protection of hippocampal neurons following kainate-induced excitotoxicity (172, 173). It is important to note that, in the absence of E2, reduced metabolites of P4 can protect against neuron loss and behavioral impairment induced by kainate (174176). In the aged female rat, P4 blocked E2-mediated increases in neurotrophic factors including BDNF, NGF and NT3 in the entorhinal cortex (177). While either E2 or P4 alone was found to promote brain mitochondrial function in OVX rats, mitochondrial function diminished when E2 and P4 were co-administered compared to either hormone alone (178). Further, while E2 alone has been found to increase levels of the anti-apoptotic factor Bcl-2, co-administration of P4 blocks this increase (179). P4 may also attenuate some of the protective effects of E2 on AD-related neuropathology, since E2+P4 co-administration to OVX 3x-TgAD mice blocked E2-mediated reductions in Abeta accumulation (124). Despite increased Abeta deposition in E2+P4 treated mice, working memory performance was similarly improved in E2 alone and E2+P4 treated mice. Interestingly, combined E2+P4 treatment reduced tau hyperphosphorylation compared to E2 alone (124).

In some paradigms, P4 improves rather than blunts protective estrogen actions. For example, in primary cultures of hippocampal neurons, the combination of E2 and P4 potentiated neuroprotection against glutamate toxicity compared to administration of either hormone alone (180). In female rats, P4 has been found to initially potentiate E2 mediated increases in hippocampal spine density, however, this was followed by a depletion of spine density to lower levels than those observed in untreated OVX rats (181). Other studies have found E2 combined with P4 to be equally protective as E2 alone following kainate lesion (182) and cerebral ischemia (183).

One key parameter that affects interactions between E2 and P4 is whether the hormones are delivered in a continuous or cyclic manner. For example, Gibbs et al. (184) found that cyclic E2+P4 administration improved cholinergic function to a greater extent than a continuous E2+P4 administration regimen. Similarly, other studies typically report benefits of P4 administered via injection, mimicking a cyclic regimen (182, 183), whereas prolonged, continuous delivery of P4 has been associated with attenuation of neuroprotective E2 effects (124, 172, 173). In female 3xTg-AD mice depleted of endogenous sex hormones by OVX, the Abeta-reducing actions of continuous E2 were blocked by continuous P4 (124, 185), but improved by cyclic P4 (185). Recently, we compared the effects of continuous versus cyclic P4 treatment regimens on neuroprotection in the entorhinal cortex following perforant path lesion, finding continuous P4 attenuated the neuroprotective effects of E2, while cyclic P4 potentiated E2-mediated neuroprotection (AMB and CJP, unpublished observations). Whether the apparent benefits of cyclic progestogen delivery suggested by recent animal studies translate to more efficacious HT in women is currently being evaluated by two ongoing clinical trials, the Early versus Late Intervention Trial with Estrogen (186) and the Kronos Early Estrogen Prevention Study (186, 187).

Although the mechanisms underlying interactions between P4 and E2 remain to be completely defined, one important area of interaction may regulation of hormone receptor expression. It is well established that levels of ERs and PRs are regulated by both E2 and P4 and that these actions can contribute to interactive hormone effects (188, 189). For example, in primary neuron cultures, P4 rapidly induced significant decreases in both ERalpha and ERbeta mRNA levels as well as reduction in ER-dependent transcriptional activity and E2 protection against apoptosis (190). Similarly, studies in cultured hippocampal slices showed that P4 blocked E2-induced increases in ERbeta expression, BDNF levels, and protection from excitotoxic challenge (191). In animal models, E2 and P4 are also associated with alterations in ERs as well as PRs, although some responses appear to be region-specific (192197). Continued research is needed to further define molecular mechanisms underlying E2 and P4 interactions particularly as they relate to regulation of AD.

5. HORMONE THERAPY & AD

Since (1) age-related depletion of sex hormones is associated with increased AD risk, and (2) sex hormones induce specific protective actions against AD, the use of estrogen- and androgen-based hormone therapies (HT) would appear to be an obvious and effective strategy to prevent as well as treat AD. However, HT is characterized by decidedly mixed success in terms of mitigating AD risk. Although HT still retains abundant therapeutic promise, additional basic and clinical efforts are needed to realize effective use of HT as a strategy to combat AD.

While early observational and small clinical studies suggested improved cognitive abilities women with AD using estrogen-based HT (198201), larger clinical trials later reported no cognitive benefit of HT (202205). Although the majority of evidence suggests estrogen-based HT does not provide any benefit in the treatment of AD, the preventative potential of HT remains controversial. Numerous reports suggest that postmenopausal women treated with HT are significantly less likely to develop AD than women not receiving HT, and AD risk may be negatively associated with dose and duration of HT use (206216). Although, some epidemiological studies report no benefit of HT on AD risk (217), these discrepancies may in part be explained by insufficient duration of HT use. For example, the Cache County Study found the greatest reduction in AD risk when HT use exceeded 10 years (212). Meta-analyses suggest that HT may reduce AD risk in the magnitude of 29–44% (218, 219). Yet the Women’s Health Initiative Memory Study (WHIMS), a large randomized, double blind, placebo-controlled study reported that HT does reduce AD risk (220, 221) and may actually increase the risk of dementia (222).

To reconcile findings from a wealth of supportive findings prior clinical studies and experimental studies indicating beneficial actions of estrogens with the apparent failure of the WHIMS to confirm a protective role of HT against AD, researchers have focused their efforts on understanding the key underlying conceptual and methodological issues. Several aspects of HT have been considered, including route of HT administration (oral versus transdermal), HT regimen (continuous versus cyclic) and HT formulation (conjugated equine estrogens versus E2, interactions between E2 and progestogens) (reviewed 223). Perhaps the most significant issue is the age at which HT is initiated. An increasingly popular theory is that the onset of menopause represents a ‘window of opportunity’ during which HT must be initiated in order to realize successful neural outcomes (101, 223, 224). According to this argument, the failure of the WHIMS and select other studies to yield protection from AD is largely due to the initiation of HT many years after menopause. Consistent with this position, recent evidence demonstrated that risk of dementia in women was significantly lessened by HT use in middle age but significantly elevated by HT use in late life (225).

In contrast to the numerous studies examining the efficacy of HT in postmenopausal women, relatively few studies have evaluated testosterone-based HT for the prevention or treatment of dementia in men. Androgen therapies have been approved for the treatment of some aspects of symptomatic androgen deficiency (ADAM), including the improvement of sexual function, psychological wellbeing, muscle mass, and bone density (226). Among the few available clinical studies of testosterone-based HT and AD, there is no data regarding the effects of HT on modifying AD risk but there is evidence that HT may provide therapeutic benefit in the management of AD. Improved spatial memory was observed in men with mild cognitive impairment and AD following six weeks of intramuscular testosterone injections (227). In a small placebo controlled clinical trial, improved quality of life and visuospatial function were observed in men with mild AD following 24 weeks of testosterone administration (228). In another small study, marked improvements in performance on the Mini Mental Status Examination and Alzheimer’s Disease Assessment Scale cognitive subscale were observed in hypogonadal AD men administered testosterone compared to placebo-treated hypogonadal AD sufferers (229). While these studies are promising, large scale clinical trials need to be carried out before definitive conclusions can be drawn regarding the therapeutic or preventative potential of testosterone HT for AD. However, drawing on the experience of the outcomes of the WHIMS trials, methodological issues including delivery, formulation, administration regime, and age at initiation should be thoroughly assessed in experimental models prior to initiation of large-scale clinical trials to allow smooth translation to the clinical setting. In addition to androgen therapy for men, androgen combined with E2 therapy has also been assessed in women for the management of menopausal symptoms to improve sexual function, relieve hot flushes, improve bone density and lipoprotein profiles (reviewed 230). Whether androgen/estrogen combined HT could provide protection against AD has not been assessed, however some evidence suggests androgens are depleted in both the male and the female AD brain (27).

5.1. Hormone therapy and the aging brain

An important corollary of the ‘window of opportunity’ theory of HT is that protective actions of sex hormones may be muted in the aging brain. Reduced efficacy of HT in aged women is observed in several systems including bone (231) and endothelium (232). Experimental evidence in animal models supports the notion that the aging brain may also respond to the sex hormones differently than the young brain. While E2 administration decreased leakiness of the blood brain barrier in young adult OVX rats, E2 increased leakiness in reproductively senescent rats (233). In young OVX rats, long term but not short term E2 administration increases spine density in the dentate gyrus, but in aged-OVX rats, short-term but not long term E2 administration increased spine density (234). E2 administration has also been found to differentially alter the synaptic distribution of the N-methyl-D-aspartate glutamatergic receptors in the hippocampus of young compared to aged-OVX rats (235). Further, E2 treatment increases expression of the neurotrophins and neurotrophin receptors in the forebrain of young but not middle-aged rats (236).

Some behavioral effects of E2 may also be age-dependent, with improved T-maze performance observed following E2 treatment in young adult but not reproductively senescent rats challenged with the muscarinic receptor antagonist scopolamine (237). While OVX impaired spatial learning and memory performance in the Morris water maze in young-adult rats, OVX did not alter performance in middle-aged rats (238). Further, E2 replacement provided diminished benefits to water maze performance in middle aged compared to young OVX rats (238).

Although some E2 effects are diminished or altered in the aging brain, other E2 actions are conserved. For example, E2 increases choline acetyltransferase expression in both young and aged female rats (239). More recently, comparison of gene expression profiles by microarray in young and middle-aged mice revealed that E2 treatment reversed transcriptional markers of brain aging in middle-aged mice (240).

E2 also differentially modulates injury responses in young and reproductively senescent rats. For example, following perforant path deafferentation, OVX reduced hippocampal sprouting in young but not middle aged rats (241). The effects of E2 on inflammatory responses may also be modulated by age since E2 administration reduced expression of the pro-inflammatory interleukin IL-1beta following excitotoxic insult in young adult but not reproductively senescent rats (242). E2 also suppresses lipopolysaccharide-induced inflammatory cytokine expression in young adult but not reproductively senescent rats (243). Some evidence suggests that while protective in young animals, E2 may even elicit some detrimental effects in reproductively senescent animals. For example, E2 replacement decreased GFAP mRNA expression in young adult rats following perforant path transection, but increased GFAP mRNA expression in middle-aged rats (241). E2 was also found to increase severity of lesion following ischemic stroke in reproductively senescent rats, despite proving protective in young adult rats (244). In contrast, others report that E2-treated rats exhibited reduced lesion size following ischemic stroke in 9–12 month-old (245) and 16 month-old (246) female rats. However, since the acyclicity of these rats was not confirmed in the studies where neuroprotection was observed, it is possible that they may have been of heterogeneous cyclicity (245, 246).

At least some of the age-related changes in response to E2 may be the result of age-related changes in expression and/or subcellular distribution of ERs. Decreased E2 binding in nuclear extracts of middle-aged rats was the first evidence of age-related changes in ER expression and distribution (247, 248). Decreased ERalpha and ERbeta levels have since been reported in the hippocampus of aged female rats (249, 250) and the cerebral cortex of aged mice (251, 252). In aged rats, reduced expression of both ERalpha and ERbeta is observed at the pre- and post-synaptic densities (249), and up to 50% fewer spines have been found to contain ERalpha in rat hippocampus (253). Further, while the hippocampal expression of both ERalpha and ERbeta increased following E2 treatment in young adult rats, E2 up regulates hippocampal expression of ERbeta but not ERalpha in aged rats (249). In contrast, in female human tissue, an age-related increase in ERalpha immunoreactivity has been observed in hippocampus (254).

In addition to altering sex hormone signaling mechanisms, aging also results in extended periods of hormone depletion, which in turn appear to limit efficacy of any future hormone treatment. That is, the absence of sex hormones can diminish neural responsiveness to beneficial hormone actions. In female rodents, the duration since OVX alters the efficacy of E2 treatment on hippocampal-dependent learning and memory performance (170, 255), spine density (256) and markers of cholinergic function (257). For example, improved spatial memory was observed in rats in the T-maze when E2 was administered 3 months, but not 10 months following OVX (170). Similarly, improved spatial memory performance in the radial arm maze was observed in rats administered E2 immediately but not 5 months following OVX (255). Daniel and colleagues demonstrated that E2 replacement increased hippocampal choline acetyltransferase levels when immediately administered to OVX rats, but not after a 5 month delay (257). The effects of E2 on ER expression may also change depending on the duration of hormone depletion. In middle aged rats, hippocampal ERalpha expression was increased when E2 treatment was initiated immediately following OVX increases, but not when E2 was delayed for 5 months (258).

Although less well studied, it appears that the aging male brain may also exhibit altered responsiveness to sex hormones. Most of the research on androgens and brain aging is in the area of sexual behaviors, which are positively regulated by androgen activation of androgen receptors (AR) (259). Aged male rats exhibit diminished sexual behavior that is not effectively restored by testosterone treatment (260, 261), suggesting age-related dysfunction in androgen signaling. Consistent with this possibility, in comparison to young adult male, aged male rats show low levels of nuclear AR binding that is poorly improved by testosterone treatment (262). Aged men also show evidence of similar androgen signaling disruption as indicated by age related decline of AR mRNA expression in hippocampus (263). Although the time course and underlying mechanisms of age-related changes in androgen signaling are incompletely defined, it appears that testosterone treatment is effective in middle-aged male rats in terms of regulating both AR expression and sexual behavior (259, 264). Key variables in this relationship likely include the age at which androgen treatment is initiated and the treatment duration required to retain and/or restore age-impaired androgen functions (265267). The extent to which neuroprotective androgen signaling is altered by aging and how such changes could impact HT in aging men are significant issues that must be addressed by future research.

5.2. SERMs and SARMs: Alternatives to conventional hormone therapies

While research continues in the optimization of parameters which may determine the efficacy of estrogen-based HT for the prevention of AD in women, deleterious effects of HT including increased risk of breast cancer, cardiovascular disease and stroke (268) has lead to the investigation of the neuroprotective effects of selective estrogen receptor modulators (SERMS) as the next generation of HT (reviewed 269). SERMS elicit tissue-specific agonist and antagonistic effects. For example, the SERM raloxifene is currently used in the treatment of osteoporosis, acting as a partial estrogen agonist to prevent bone loss, while functioning as an antiestrogen in breast and endometrial tissue (270272). In cultured neurons, low doses of raloxifene were neuroprotective against toxicity induced by Abeta, hydrogen peroxide, and glutamate (273). Raloxifene also exhibits neurotrophic effects, promoting neurite outgrowth in both PC12 cells (274) and primary neuronal cultures (273). However, raloxifene applied to neuronal cultures in combination with E2, partially inhibited the neuroprotective effects of E2 (273). In rodents, raloxifene mimicked the protective effects of E2 in a mouse model of Parkinson’s disease, whereas the SERM tamoxifen partially antagonized E2 protection (275). Tamoxifen, a SERM widely used to antagonize E2 in the treatment of breast cancer, is known to block E2-mediated neuroprotection in cultures of primary neurons (276) and PC12 cells (277).

Evidence from human studies also suggests that raloxifene and tamoxifen may exhibit mixed estrogen agonist-antagonist effects in the brain. In postmenopausal women, no effect of raloxifene was observed on measures of depression, mood, and cognition following 1 year of use (278). However, in a randomized, placebo-controlled study of raloxifene administered for 3 years, the SERM was associated with a marked reduction in the risk of cognitive impairment and a mild reduction in AD risk (279). Raloxifene may increase the risk of hot flashes, suggesting an antagonist action on ER effects of vasomotor function (280, 281). Tamoxifen use has also been associated with reduced AD risk and increased independence and decision-making amongst nursing home residents (282). Further, similar profiles of markers of brain metabolism have been observed in HT and tamoxifen users compared to non-users, perhaps indicating E2 agonist effects of tamoxifen in the human brain (283). Yet, a study of breast cancer patients found increased reports of memory problems in long-term tamoxifen users (284) and impaired verbal memory (285). Because currently utilized SERMs have mixed estrogenic effects in brain, ongoing efforts have focused on the development of new SERMS that exert neuroprotective effects in the absence of oncogenic effects in reproductive tissues.

The selective ER subtype agonists propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenol) proprionitrile (DPN), which are relatively selective for ERalpha and ERbeta respectively (286, 287), have been investigated as potential neuroprotective SERMS. Since ERbeta is expressed throughout the brain but at low levels in reproductive tissues including breast and uterus (288), compounds such as DPN may offer neuroprotective estrogenic effects in the absence of detrimental effects on reproductive tissues (reviewed 289). However, in primary hippocampal cultures, PPT but not DPN mimicked E2 and increased synaptic density (290). In primary neuronal cultures both PPT and DPN have been found to decrease expression of the pro-apoptotic proteins and protect against glutamate (291) and Abeta-mediated cell death (292). Mixed effects of PPT and DPN have been reported in models of ischemic injury. PPT, but not DPN, was found to provide reduce cell loss in the CA1 region following ischemia in rats (293, 294). However, in mice, DPN but not PPT reduced cell loss in caudate nucleus and CA1 following global ischemia (295). In OVX 3xTg-AD mice, PPT was superior to DPN in terms of mimicking E2 effects of decreasing Abeta accumulation and improving behavioral deficits (123).

Like estrogen-based HT in women, testosterone-based HT in men is associated with potential risks. In particular, testosterone HT may have adverse effects on prostate, most notably the potential for promoting growth and/or risk of prostate tumors (5). The need for HT in men that yields androgen benefits on bone, muscle and brain but avoids deleterious consequences in prostate has driven research to develop tissue-specific selective androgen receptor modulators (SARMs). There have been several strategies in SARM development, including synthetic AR ligands that are not substrates for 5alpha-reductase and compounds that exhibit altered interaction with AR binding pocket side chains that underlie tissue specificity (296300). Recent preclinical evidence suggests significant progress in identifying suitable candidate SARMs that exert androgenic effects on muscle at doses that do not significantly affect prostate and other reproductive tissues (300302). Evaluation of SARMs for use neural endpoints is an essentially unexplored area, but a topic currently under investigation in the authors’ laboratory.

6. PERSPECTIVE

Because AD is a disease of aging, understanding how aging promotes the disease process represents a potentially powerful approach for developing strategies to delay and perhaps prevent the disease. In this context, the normal age-related losses of sex steroid hormones in men and women appear to be significant events. In fact, abundant evidence demonstrates that low levels of sex hormones, estrogens in women and testosterone in men, are risk factors for development of AD. Basic research has identified and mechanistically characterized numerous protective actions of sex hormones that improve neural functioning and resilience and may antagonize AD pathogenesis. Not only do sex hormones increase neural plasticity and improve aspects of cognition, they also protect neurons from cell death induced by a range of toxic insults. Most importantly, sex hormones are endogenous negative regulators of Abeta, the accumulation of which initiates and drives AD cascades. Together, these lines of evidence argue that estrogen HT in women and testosterone HT men should effectively reduce AD risk and promote neural health.

Although the theory that sex hormones can protect against AD is a compelling one, clinical demonstration of HT efficacy has shown only mixed success. First, it appears that the potential benefits of estrogen- and testosterone-based HTs are largely limited to prevention rather than treatment of AD. Even in this case, emerging research indicates that there are several variables that likely impact the efficacy of HT. For example, optimal results may require that hormones be delivered transdermally rather than the traditional oral route. In addition, HT may be expected to have different effects depending upon whether it is delivered continuously or cyclically. Although sex hormone levels naturally fluctuate, testosterone rising and falling in a diurnal rhythm and E2 and P4 across the monthly ovarian cycle, the failure of HT to match the natural cyclicity of hormone levels may undermine its ability to appropriately restore normal hormone actions. Further, in the case of estrogen HT, the role of progestogens requires additional definition. New findings indicate that natural P4 and synthetic progestogens can attenuate or accentuate protective E2 actions depending upon their delivery.

Perhaps the most daunting obstacle to overcome in assessing the therapeutic potential of sex hormones is the role of aging. A key variable in the negative outcome of several HT studies appears to be the advanced age at which HT was initiated. Recent research indicates that aging male and female brains have altered, typically diminished responsiveness to sex hormones that is not ameliorated by hormone treatment during old age. Thus, efficacious HT may require initiation during middle age, a time at which sex hormone depletion is significant and yet the brain retains hormone responsiveness. However, definitive clinical evidence of that initiation of HT in middle age reduces AD risk in old age would require many years. Even in this case, important issues would need to be resolved. How long must HT be maintained in order to realize benefits, five years, ten years, more? Since prolonged HT use seems likely, adverse effects of sex hormones must be considered. Although sex hormones have numerous health benefits, they are also associated with risks including promotion of cancers in reproductive tissues. This risk may be minimized by the continued refinement of new generation SERMs and SARMs, sex hormone mimetics that exert tissue-specific agonist effects. Continuing research over the next several years should provide significant insight into these issues and determine the utility of HT for protection against AD.

Acknowledgments

This work was supported by grants from the National Institute on Aging (AG05142, AG26572) and Alzheimer’s Association (IIRG-10-174301). AMB was supported by the American-Australian Association and the Japan Society for the Promotion of Science.

References

1. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, Brayne C, Copeland JRM, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. The Eurodem Incidence Research Group and Work Groups. Rates and risk factors for dementia and Alzheimer’s disease. Neurology. 1999;52(1):78–78. No doi match found. [PubMed]
2. Ritchie K, Kildea D. Is senile dementia “age-related” or “ageing-related”? -evidence from meta-analysis of dementia prevalence in the oldest old. Lancet. 1995;346(8980):931–934. doi: 10.1016/S0140-6736(95)91556-7. [PubMed] [Cross Ref]
3. Alzheimer’s-Association. Alzheimer’s disease facts and figures. Alz Dementia. 2010;6(2):158–194. doi: 10.1016/j.jalz.2010.01.009. 2010. [PubMed] [Cross Ref]
4. Morley JE. Androgens and aging. Maturitas. 2001;38(1):61–73. doi: 10.1016/S0378-5122(00)00192-4. [PubMed] [Cross Ref]
5. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26(6):833–76. doi: 10.1210/er.2004-0013. [PubMed] [Cross Ref]
6. Gooren L. Androgen deficiency in the aging male: benefits and risks of androgen supplementation. J Steroid Biochem Mol Biol. 2003;85(2–5):349–55. doi: 10.1016/S0960-0760(03)00206-1. [PubMed] [Cross Ref]
7. Burger HG, de Laet CE, van Daele PL, Weel AE, Witteman JCM, Hofman A, Pols HAP. Risk factors for increased bone loss in an elderly population: the Rotterdam Study. Am J Epidemiol. 1998;147(9):871–9. No doi match found. [PubMed]
8. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderlymen and women. Mech Ageing Dev. 1999;107(2):123–36. doi: 10.1016/S0047-6374(98)00130-4. [PubMed] [Cross Ref]
9. Jones RD, Pugh PJ, Hall J, Channer KS, Jones TH. Altered circulating hormone levels, endothelial function and vascular reactivity in the testicular feminised mouse. Eur J Endocrinol. 2003;148(1):111–20. doi: 10.1530/eje.0.1480111. [PubMed] [Cross Ref]
10. Sheffield-Moore M, Urban RJ. An overview of the endocrinology of skeletal muscle. Trends Endocrinol Metab. 2004;15(3):110–5. doi: 10.1016/j.tem.2004.02.009. [PubMed] [Cross Ref]
11. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab. 2002;282(3):E601–7. No doi match found. [PubMed]
12. Meier DE, Orwoll ES, Keenan EJ, Fagerstrom RM. Marked decline in trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels. J Am Geriatr Soc. 1987;35(3):189–97. No doi match found. [PubMed]
13. Fillit H, Luine V. The neurobiology of gonadal hormones and cognitive decline in late life. Maturitas. 1997;26(3):159–64. doi: 10.1016/S0378-5122(97)01101-8. [PubMed] [Cross Ref]
14. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2002;87(2):589–598. doi: 10.1210/jc.87.2.589. [PubMed] [Cross Ref]
15. Gray A, Feldman H, McKinlay J, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 1991;73(5):1016–1025. doi: 10.1210/jcem-73-5-1016. [PubMed] [Cross Ref]
16. Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged, 40–80 years. Eur J Endocrinol. 2003;149(6):583–9. doi: 10.1530/eje.0.1490583. No doi match found. [PubMed] [Cross Ref]
17. Morley JE, Kaiser FE, Perry HM, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exp. 1997;46(4):410–3. doi: 10.1016/S0026-0495(97)90057-3. [PubMed] [Cross Ref]
18. Vermeulen A. Clinical problems in reproductive neuroendocrinology of men. Neurobiol Aging. 1994;15(4):489–493. doi: 10.1016/0197-4580(94)90085-X. [PubMed] [Cross Ref]
19. Mastrogiacomo I, Geghali G, Foresta C, Ruzza G. Andropause: Incidence and pathogenesis. Arch Androl. 1982;9(4):293–296. doi: 10.3109/01485018208990253. [PubMed] [Cross Ref]
20. Tenover JL. Male hormone replacement therapy including ‘andropause’ Endocrinol Metab Clin Noth Am. 1998;27(4):969–987. doi: 10.1016/S0889-8529(05)70050-5. [PubMed] [Cross Ref]
21. Bassil N, Morley JE. Late-Life Onset Hypogonadism: A Review. Clin Geriatr Med. 2010;26(2):197–222. doi: 10.1016/j.cger.2010.02.003. [PubMed] [Cross Ref]
22. Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE. Andropause: a quality-of-life issue in older males. Med Clin North Am. 2006;90(5):1005–1023. doi: 10.1016/j.mcna.2006.06.001. [PubMed] [Cross Ref]
23. Morley JE, Perry HM. Androgen Deficiency in Aging Men. Med Clin North Am. 1999;83(5):1279–1289. doi: 10.1016/S0025-7125(05)70163-2. [PubMed] [Cross Ref]
24. Stoffel-Wagner B. Neurosteroid metabolism in the human brain. Eur J Endocrinol. 2001;145(6):669–679. doi: 10.1530/eje.0.1450669. [PubMed] [Cross Ref]
25. Melcangi RC, Panzica GC. Neuroactive steroids. Old players in a new game. Neuroscience. 2006;138(3):733–739. doi: 10.1016/j.neuroscience.2005.10.066. [PubMed] [Cross Ref]
26. Manni A, William M, Cefalu W, Nisula BC, Bardin CW, Santner SJ, Santen RJ. Bioavailability of albumin-bound testosterone. J Clin Endocrinol Metab. 1985;61(4):705–710. doi: 10.1210/jcem-61-4-705. [PubMed] [Cross Ref]
27. Rosario ER, Chang L, Head EH, Stanczyk FZ, Pike CJ. Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease. Neurobiol Aging. 2011;32:604–613. No doi match found. [PMC free article] [PubMed]
28. Bixo M, Backstrom T, Winblad B, Andersson A. Estradiol and testosterone in specific regions of the human female brain in different endocrine states. J Steroid Biochem Mol Biol. 1995;55(3–4):297–303. doi: 10.1016/0960-0760(95)00179-4. [PubMed] [Cross Ref]
29. Rosario ER, Chang L, Stanczyk FZ, Pike CJ. Age-related testosterone depletion and the development of Alzheimer disease. J Am Med Assoc. 2004;282(12):1431–1432. doi: 10.1001/jama.292.12.1431-b. [PubMed] [Cross Ref]
30. Harman S, Tsitouras P, Costa P, Blackman M. Reproductive hormones in aging men. II. Basal pituitary gonadotropins and gonadotropin responses to luteinizing hormone-releasing hormone. J Clin Endocrinol Metab. 1982;54(3):547–551. doi: 10.1210/jcem-54-3-547. [PubMed] [Cross Ref]
31. Rosario ER, Chang L, Beckett TL, Carroll JC, Murphy PM, Stanczyk FZ, Pike CJ. Age-related changes in serum and brain levels of androgens in male Brown Norway rats. Neuroreport. 2009;20(17):1534–1537. doi: 10.1097/WNR.0b013e328331f968. [PubMed] [Cross Ref]
32. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1–2):125–132. doi: 10.1159/000109998. [PMC free article] [PubMed] [Cross Ref]
33. Woo J, Lee J, Yoo K, Kim C, Kim Y, Shin Y. Prevalence estimation of dementia in a rural area of Korea. J Am Geriatr Soc. 1998;46(8):983–7. No doi match found. [PubMed]
34. Graves AB, Larson EB, Edland SD, Bowen JD, McCormick WC, McCurry SM, Rice MM, Wenzlow A, Uomoto JM. Prevalence of dementia and Its subtypes in the Japanese American population of King County, Washington State. Am J Epidemiol. 1996;144(8):760–771. No doi match found. [PubMed]
35. López Pousa S, Llinás Regla J, Vilalta Franch J, Lozano Fernández de Pinedo L. The prevalence of dementia in Girona. Neurologia. 1995;10(5):189–93. No doi match found. [PubMed]
36. Folstein MF, Bassett SS, Anthony JC, Romanoski AJ, Nestadt GR. Dementia: case ascertainment in a community survey. J Gerontol. 1991;46(4):M132–M138. No doi match found. [PubMed]
37. Canadian Study of Health and Aging Working Group. Canadian study of health and aging: study methods and prevalence of dementia. Can Med Assoc J. 1994;150(6):899–913. No doi match found. [PMC free article] [PubMed]
38. Bachman DL, Wolf PA, Linn R, Knoefel JE, CobbS J, Belanger A, D’Agostino RB, White LR. Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology. 1992;42(1):115–115. No doi match found. [PubMed]
39. Rocca WA, Amaducci LA, Schoenberg BS. Epidemiology of clinically diagnosed Alzheimer’s disease. Ann Neurol. 1986;19(5):415–24. doi: 10.1002/ana.410190502. [PubMed] [Cross Ref]
40. Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B. Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology. 1997;48(1):132–8. No doi match found. [PubMed]
41. Hagnell O, Ojesjo L, Rorsman B. Incidence of dementia in the Lundby Study. Neuroepidemiology. 1992;11(Suppl 1):61–6. doi: 10.1159/000110981. [PubMed] [Cross Ref]
42. Molsa PK, Marttila RJ, Rinne UK. Epidemiology of dementia in a Finnish population. Acta Neurol Scand. 1982;65(6):541–52. doi: 10.1111/j.1600-0404.1982.tb03109.x. [PubMed] [Cross Ref]
43. Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MMB. Incidence of dementia: does gender make a difference? Neurobiol Aging. 2001;22(4):575–580. doi: 10.1016/S0197-4580(01)00231-7. [PubMed] [Cross Ref]
44. Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psych. 1998;55(9):809–815. doi: 10.1001/archpsyc.55.9.809. [PubMed] [Cross Ref]
45. Hogervorst E, Matthews FE, Brayne C. Are optimal levels of testosterone associated with better cognitive function in healthy older women and men? Biochim Biophys Acta. 2010;1800(10):1145–1152. No doi match found. [PubMed]
46. Hogervorst E, Boshuisen M, Riedel W, Willeken C, Jolles J. The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology. 1999;24(1):43–68. doi: 10.1016/S0306-4530(98)00043-2. [PubMed] [Cross Ref]
47. Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, D’Agostino RB, White LR. Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology. 1992;42(1):115–9. No doi match found. [PubMed]
48. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76(5):465–79. doi: 10.1111/j.1600-0447.1987.tb02906.x. [PubMed] [Cross Ref]
49. Brayne C, Gill C, Huppert FA, Barkley C, Gehlhaar E, Girling DM, O’Connor DW, Paykel ES. Incidence of clinically diagnosed subtypes of dementia in an elderly population. Cambridge Project for Later Life. Br J Psychiatry. 1995;167(2):255–62. doi: 10.1192/bjp.167.2.255. [PubMed] [Cross Ref]
50. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. J Am Med Assoc. 1997;278(16):1349–56. doi: 10.1001/jama.278.16.1349. [PubMed] [Cross Ref]
51. Buckwalter JG, Sobel E, Dunn ME, Diz MM, Henderson VW. Gender differences on a brief measure of cognitive functioning in Alzheimer’s disease. Arch Neurol. 1993;50(7):757–760. No doi match found. [PubMed]
52. Henderson V, Buckwalter J. Cognitive deficits of men and women with Alzheimer’s disease. Neurology. 1994;44(1):90–96. No doi match found. [PubMed]
53. Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005;62(6):685–91. doi: 10.1001/archpsyc.62.6.685. [PubMed] [Cross Ref]
54. Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H. The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann NY Acad Sci. 2004;1019:24–8. doi: 10.1196/annals.1297.005. [PubMed] [Cross Ref]
55. Schultz C, Braak H, Braak E. A sex difference in neurodegeneration of the human hypothalamus. Neurosci Lett. 1996;212(2):103–6. doi: 10.1016/0304-3940(96)12787-7. [PubMed] [Cross Ref]
56. Schultz C, Ghebremedhin E, Braak E, Braak H. Sex-dependent cytoskeletal changes of the human hypothalamus develop independently of Alzheimer’s disease. Exp Neurol. 1999;160(1):186–93. doi: 10.1006/exnr.1999.7185. [PubMed] [Cross Ref]
57. Lee C, Colegate S, Fisher AD. Development of a maze test and its application to assess spatial learning and memory in Merino sheep. Appl Anim Behav Sci. 2006;96(1–2):43–51. doi: 10.1016/j.applanim.2005.06.001. [Cross Ref]
58. Callahan MJ, Lipinski WJ, Bian F, Durham RA, Pack A, Walker LC. Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice. Am J Pathol. 2001;158(3):1173–7. doi: 10.1016/S0002-9440(10)64064-3. [PubMed] [Cross Ref]
59. Pistell PJ, Zhu M, Ingram DK. Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease. Neuroscience. 2008;152(3):594–600. doi: 10.1016/j.neuroscience.2008.01.025. [PMC free article] [PubMed] [Cross Ref]
60. Wang J, Tanila H, Puolivali J, Kadish I, van Groen T. Gender differences in the amount and deposition of amyloid beta in APPswe and PS1 double transgenic mice. Neurobiol Dis. 2003;14(3):318–27. doi: 10.1016/j.nbd.2003.08.009. [PubMed] [Cross Ref]
61. Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, Pike CJ. Sex differences in beta-amyloid accumulation in 3xTg-AD mice: Role of neonatal sex steroid hormone exposure. Brain Res. 2010;17(1366):233–45. doi: 10.1016/j.brainres.2010.10.009. [PMC free article] [PubMed] [Cross Ref]
62. Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y. Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008;1216:92–103. doi: 10.1016/j.brainres.2008.03.079. [PubMed] [Cross Ref]
63. Toran-Allerand CD. On the genesis of sexual differentiation of the general nervous system: morphogenetic consequences of steroidal exposure and possible role of alpha-fetoprotein. Prog Brain Res. 1984;61:63–98. doi: 10.1016/S0079-6123(08)64429-5. [PubMed] [Cross Ref]
64. Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol. 2004;39(11–12):1633–1639. doi: 10.1016/j.exger.2004.06.019. [PubMed] [Cross Ref]
65. Hogervorst E, Combrinck M, Smith AD. Testosterone and gonadotropin levels in men with dementia. Neuroendocrin Lett. 2003;24(3–4):203–208. No doi match found. [PubMed]
66. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrin Lett. 2001;22(3):163–168. No doi match found. [PubMed]
67. Paoletti AM, Congia S, Lello S, Tedde D, Orru M, Pistis M, Pilloni M, Zedda P, Loddo A, Melis GB. Low androgenization index in elderly women and elderly men with Alzheimer’s disease. Neurology. 2004;62(2):301–3. No doi match found. [PubMed]
68. Watanabe T, Koba S, Kawamura M, Itokawa M, Idei T, Nakagawa Y, Iguchi T, Katagiri T. Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. Metab. 2004;53(4):476–82. doi: 10.1016/j.metabol.2003.11.020. [PubMed] [Cross Ref]
69. Manly JJ, Merchant CA, Jacobs DM, Small S, Bell K, Ferin M, Mayeux R. Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology. 2000;54(4):833–837. No doi match found. [PubMed]
70. Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endo Metab. 2002;87(11):5001–7. doi: 10.1210/jc.2002-020419. [PubMed] [Cross Ref]
71. Tsolaki M, Grammaticos P, Karanasou C, Balaris V, Kapoukranidou D, Kaldipis I, Petsansis K, Dedousi E. Serum estradiol, progesterone, testosterone, FSH and LH levels in postmenopausal women with Alzheimer’s dementia. Hell J Nucl Med. 2005;8(1):39–42. No doi match found. [PubMed]
72. Hogervorst E, Williams J, Biudge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer’s disease. Neuro Endocrinol Lett. 2001;22(3):163–168. No doi match found. [PubMed]
73. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004;62(2):188–93. [PubMed]
74. Chu L, Tam S, Wong R, Yik P, Song Y, Cheung B, Morley J, Lam K. Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men. J Alz Dis. 2010 doi: 10.1016/j.jalz.2010.05.345. In press. [PubMed] [Cross Ref]
75. Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry. 2006;60(12):1287–1294. doi: 10.1016/j.biopsych.2006.06.017. [PubMed] [Cross Ref]
76. Yue X, Lu M, Lancaster T, Cao P, Honda S-I, Staufenbiel M, Harada N, Zhong Z, Shen Y, Li R. Brain estrogen deficiency accelerates Ab plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci USA. 2005;102(52):19198–19203. doi: 10.1073/pnas.0505203102. [PubMed] [Cross Ref]
77. Luchetti S, Bossers K, Van de Bilt S, Agrapart V, Morales RR, Frajese GV, Swaab DF. Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer’s disease. Neurobiol Aging. 2009 In Press, Corrected Proof. No doi match found. [PubMed]
78. Yau JLW, Rasmuson S, Andrew R, Graham M, Noble J, Olsson T, Fuchs E, Lathe R, Seckl JR. Dehydroepiandrosterone 7-hydroxylase cyp7b: predominant expression in primate hippocampus and reduced expression in alzheimer’s disease. Neuroscience. 2003;121(2):307–314. doi: 10.1016/S0306-4522(03)00438-X. [PubMed] [Cross Ref]
79. Schaeffer V, Meyer L, Patte-Mensah C, Eckert A, Mensah-Nyagan AG. Dose-dependent and sequence-sensitive effects of amyloid-beta peptide on neurosteroidogenesis in human neuroblastoma cells. Neurochem Int. 2008;52(6):948–955. doi: 10.1016/j.neuint.2008.01.010. [PubMed] [Cross Ref]
80. Schaeffer V, Patte-Mensah C, Eckert A, Mensah-Nyagan AG. Modulation of neurosteroid production in human neuroblastoma cells by Alzheimer’s disease key proteins. J Neurobiol. 2006;66(8):868–881. doi: 10.1002/neu.20267. [PubMed] [Cross Ref]
81. Lu Y-P, Zeng M, Hu X-Y, Xu H, Swaab DF, Ravid R, Zhou J-N. Estrogen receptor alpha-immunoreactive astrocytes are increased in the hippocampus in Alzheimer’s disease. Exp Neurol. 2003;183(2):482–488. doi: 10.1016/S0014-4886(03)00205-X. [PubMed] [Cross Ref]
82. Savaskan E, Olivieri G, Meier F, Ravid R, Muller-Spahn F. Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer’s disease. Brain Res. 2001;908(2):113–9. doi: 10.1016/S0006-8993(01)02610-5. [PubMed] [Cross Ref]
83. Lu YP, Zeng M, Swaab DF, Ravid R, Zhou JN. Colocalization and alteration of estrogen receptor-alpha and -beta in the hippocampus in Alzheimer’s disease. Hum Pathol. 2004;35(3):275–80. doi: 10.1016/j.humpath.2003.11.004. [PubMed] [Cross Ref]
84. Hestiantoro A, Swaab DF. Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer’s disease neuropathology. J Clin Endocrinol Metab. 2004;89(4):1912–25. doi: 10.1210/jc.2003-030862. [PubMed] [Cross Ref]
85. Lambert J-C, Harris JM, Mann D, Lemmon H, Coates J, Cumming A, St-Clair D, Lendon C. Are the estrogen receptors involved in Alzheimer’s disease? Neurosci Lett. 2001;306(3):193–197. doi: 10.1016/S0304-3940(01)01806-7. [PubMed] [Cross Ref]
86. Ji Y, Urakami K, Wada-Isoe K, Adachi Y, Nakashima K. Estrogen Receptor Gene Polymorphisms in Patients with Alzheimer’s Disease, Vascular Dementia and Alcohol-Associated Dementia. Dement Geriatr Cogn Disord. 2000;11(3):119–122. doi: 10.1159/000017224. [PubMed] [Cross Ref]
87. Corbo RM, Gambina G, Ruggeri M, Scacchi R. Association of Estrogen Receptor alpha (ESR1) PvuII and XbaI Polymorphisms with Sporadic Alzheimer’s Disease and Their Effect on Apolipoprotein E Concentrations. Dement Geriatr Cogn Disord. 2006;22(1):67–72. doi: 10.1159/000093315. [PubMed] [Cross Ref]
88. Brandi ML, Becherini L, Gennari L, Racchi M, Bianchetti A, Nacmias B, Sorbi S, Mecocci P, Senin U, Govoni S. Association of the Estrogen Receptor alpha Gene Polymorphisms with Sporadic Alzheimer’s Disease. Biochem Biophys Res Commun. 1999;265(2):335–338. doi: 10.1006/bbrc.1999.1665. [PubMed] [Cross Ref]
89. Yaffe K, Lui L-Y, Grady D, Stone K, Morin P. Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatry. 2002;51(8):677–682. doi: 10.1016/S0006-3223(01)01289-6. [PubMed] [Cross Ref]
90. Kazama H, Ruberu NN, Murayama S, Saito Y, Nakahara Ki, Kanemaru K, Nagura H, Arai T, Sawabe M, Yamanouchi H, Orimo H, Hosoi T. Association of Estrogen Receptor alpha Gene Polymorphisms with Neurofibrillary Tangles. Dement Geriatr Cogn Disord. 2004;18(2):145–150. doi: 10.1159/000079194. [PubMed] [Cross Ref]
91. Mattila KM, Axelman K, Rinne JO, Blomberg M, Lehtimäki T, Laippala P, Röyttä M, Viitanen M, Wahlund LO, Winblad B, Lannfelt L. Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer’s disease in women. Neurosci Lett. 2000;282(1–2):45–48. doi: 10.1016/S0304-3940(00)00849-1. [PubMed] [Cross Ref]
92. Porrello E, Monti MC, Sinforiani E, Cairati M, Guaita A, Montomoli C, Govoni S, Racchi M. Estrogen receptor α and APOE 4 polymorphisms interact to increase risk for sporadic AD in Italian females. Eur J Neurol. 2006;13(6):639–644. doi: 10.1111/j.1468-1331.2006.01333.x. [PubMed] [Cross Ref]
93. Ishunina TA, Swaab DF. Decreased alternative splicing of estrogen receptor-alpha mRNA in the Alzheimer’s disease brain. Neurobiol Aging. 2010 In Press, Corrected Proof. No doi match found. [PubMed]
94. Lehmann DJ, Butler HT, Warden DR, Combrinck M, King E, Nicoll JAR, Budge MM, de Jager CA, Hogervorst E, Esiri MM, Ragoussis J, Smith AD. Association of the androgen receptor CAG repeat polymorphism with Alzheimer’s disease in men. Neurosci Lett. 2003;340(2):87–90. doi: 10.1016/S0304-3940(03)00069-7. [PubMed] [Cross Ref]
95. Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, Hatanaka Y, Ogiue-Ikeda M. Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim Biophys Acta. 2010;1800(10):1030–1044. No doi match found. [PubMed]
96. Hajszan T, MacLusky NJ, Leranth C. Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav. 2008;53(5):638–646. doi: 10.1016/j.yhbeh.2007.12.007. [PMC free article] [PubMed] [Cross Ref]
97. Spencer JL, Waters EM, Romeo RD, Wood GE, Milner TA, McEwen BS. Uncovering the mechanisms of estrogen effects on hippocampal function. Front Neuroendocrinol. 2008;29(2):219–237. doi: 10.1016/j.yfrne.2007.08.006. [PMC free article] [PubMed] [Cross Ref]
98. Foy MR. Ovarian hormones, aging and stress on hippocampal synaptic plasticity. Neurobiol Learn Mem. 2011;95(2):134–44. doi: 10.1016/j.nlm.2010.11.003. [PMC free article] [PubMed] [Cross Ref]
99. Toran-Allerand CD, Singh M, Setalo G., Jr Novel mechanisms of estrogen action in the brain: new players in an old story. Front Neuroendocrinol. 1999;20(2):97–121. doi: 10.1006/frne.1999.0177. [PubMed] [Cross Ref]
100. Janowsky JS. The role of androgens in cognition and brain aging in men. Neuroscience. 2006;138(3):1015–1020. doi: 10.1016/j.neuroscience.2005.09.007. [PubMed] [Cross Ref]
101. Sherwin BB. Estrogen and cognitive functioning in women. Endocr Rev. 2003;24(2):133–151. doi: 10.1210/er.2001-0016. [PubMed] [Cross Ref]
102. Cherrier M. Testosterone effects on cognition in health and disease. Front Horm Res. 2009;37(150–62) doi: 10.1159/000176051. [PubMed] [Cross Ref]
103. Driscoll I, Resnick S. Testosterone and cognition in normal aging and Alzheimer’s disease: an update. Curr Alz Res. 2007;4(1):33–45. doi: 10.2174/156720507779939878. [PubMed] [Cross Ref]
104. Moffat SD. Effects of testosterone on cognitive and brain aging in elderly men. Ann NY Acad Sci. 2005;1055(1):80–92. doi: 10.1196/annals.1323.014. [PubMed] [Cross Ref]
105. Sherwin BB. Estrogen and cognitive aging in women. Neuroscience. 2006;138(3):1021–1026. doi: 10.1016/j.neuroscience.2005.07.051. [PubMed] [Cross Ref]
106. Henderson VW. Cognitive Changes After Menopause: Influence of Estrogen. Clin Obstet Gynecol. 2008;51(3):618–626. doi: 10.1097/GRF.0b013e318180ba10. [PMC free article] [PubMed] [Cross Ref]
107. Luine VN. Sex steroids and cognitive function. J Neuroendocrinol. 2008;20(6):866–72. doi: 10.1111/j.1365-2826.2008.01710.x. [PubMed] [Cross Ref]
108. 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. doi: 10.1016/j.yfrne.2009.04.015. [PMC free article] [PubMed] [Cross Ref]
109. Pike CJ, Nguyen T-VV, Ramsden M, Yao M, Murphy MP, Rosario ER. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav. 2008;53(5):693–705. doi: 10.1016/j.yhbeh.2007.11.006. [PMC free article] [PubMed] [Cross Ref]
110. Perez E, Wang X, Simpkins JW. Role of antioxidant activity of estrogens in their potent neuroprotection. In: Qureshi GA, Parvez SH, editors. Oxidative Stress and Neurodegenerative Disorders. Elsevier Science B.V; Amsterdam: 2007. No doi match found.
111. Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30(2):201–211. doi: 10.1016/j.yfrne.2009.04.007. [PubMed] [Cross Ref]
112. Raber J. Androgens, apoE, and Alzheimer’s disease. In: Sun M-K, editor. Research Progress in Alzheimer’s Disease. Nova Science Publishers; United States: 2004. No doi match found.
113. Schönknecht P, Pantel J, Klinga K, Jensen M, Hartmann T, Salbach B, Schröder J. Reduced cerebrospinal fluid estradiol levels are associated with increased beta-amyloid levels in female patients with Alzheimer’s disease. Neurosci Lett. 2001;307(2):122–124. doi: 10.1016/S0304-3940(01)01896-1. [PubMed] [Cross Ref]
114. Baker LD, Sambamurti K, Craft S, Cherrier M, Raskind MA, Stanczyk FZ, Plymate SR, Asthana S. 17beta-estradiol reduces plasma Abeta40 for HRT-naive postmenopausal women with Alzheimer disease: a preliminary study. Am J Geriatr Psychiatry. 2003;11(2):239–44. No doi match found. [PubMed]
115. Gandy S, Almeida OP, Fonte J, Lim D, Waterrus A, Spry N, Flicker L, Martins RN. Chemical andropause and amyloid-beta peptide. J Am Med Assoc. 2001;285(17):2195–2196. doi: 10.1001/jama.285.17.2195-a. [PubMed] [Cross Ref]
116. Almeida O, Waterreous A, Spry N, Flicker L, Martins RN. One year follow-up study of the association between chemical castration,sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology. 2004;29(8):1071–1081. doi: 10.1016/j.psyneuen.2003.11.002. [PubMed] [Cross Ref]
117. Gillett MJ, Martins RN, Clarnette RM, Chubb SA, Bruce DG, Yeap BB. Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia. J Alzheimers Dis. 2003;5(4):267–9. No doi match found. [PubMed]
118. Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer’s amyloid b peptides in brain. Exp Gerontol. 2000;35:1317–1325. doi: 10.1016/S0531-5565(00)00157-1. [PubMed] [Cross Ref]
119. Zheng H, Xu H, Uljon SN, Gross R, Hardy K, Gaynor J, Lafrancois J, Simpkins J, Refolo LM, Petanceska S, Wang R, Duff K. Modulation of Ab peptides by estrogen in mouse models. J Neurochem. 2002;80(1):191. doi: 10.1046/j.0022-3042.2001.00690.x. [PubMed] [Cross Ref]
120. Levin-Allerhand JA, Lominska CE, Wang J, Smith JD. 17alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice. J Alz Dis. 2002;4(6):449–457. No doi match found. [PubMed]
121. Amtul Z, Wang L, Westaway D, Rozmahel RF. Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer’s disease. Neuroscience. 2010;169(2):781–786. doi: 10.1016/j.neuroscience.2010.05.031. [PubMed] [Cross Ref]
122. Xu H, Wang R, Zhang Y-W, Zhang X. Estrogen, beta-Amyloid metabolism/trafficking, and Alzheimer’s disease. Ann NY Acad Sci. 2006;1089:324–342. doi: 10.1196/annals.1386.036. [PubMed] [Cross Ref]
123. Carroll JC, Pike CJ. Selective estrogen receptor modulators differentially regulate Alzheimer-like changes in female 3xTg-AD mice. Endocrinology. 2008;149(5):2607–11. doi: 10.1210/en.2007-1346. [PubMed] [Cross Ref]
124. Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, LaFerla FM, Pike CJ. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007;27(48):13357–13365. doi: 10.1523/JNEUROSCI.2718-07.2007. [PubMed] [Cross Ref]
125. Golub MS, Germann SL, Mercer M, Gordon MN, Morgan DG, Mayer LP, Hoyer PB. Behavioral consequences of ovarian atrophy and estrogen replacement in the APPswe mouse. Neurobiol Aging. 2007;29(10):1512–1523. doi: 10.1016/j.neurobiolaging.2007.03.015. [PMC free article] [PubMed] [Cross Ref]
126. Barron AM, Cake M, Verdile G, Martins RN. Ovariectomy and 17beta-estradiol replacement do not alter beta-amyloid levels in sheep brain. Endocrinology. 2009;150(7):3228–3236. doi: 10.1210/en.2008-1252. [PubMed] [Cross Ref]
127. Heikkinen T, Kalesnykas G, Rissanen A, Tapiola T, Livonen S, Wang J, Chaudhuri J, Tanila H, Miettinen R, Puolivali J. Estrogen treatment improves spatial learning in APP+PS1 mice but does not affect beta amyloid accumulation and plaque formation. Exp Neurol. 2004;187(1):105–117. doi: 10.1016/j.expneurol.2004.01.015. [PubMed] [Cross Ref]
128. Green PS, Bales K, Paul S, Bu G. Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer’s disease. Endocrinology. 2005;146(6):2774–2781. doi: 10.1210/en.2004-1433. [PubMed] [Cross Ref]
129. Barron AM, Verdile G, Taddei K, Bates KA, Martins RN. Effect of chronic hCG administration on Alzheimer’s-related cognition and Abeta accumulation in PS1KI mice. Endocrinology. 2010;151(11):5380–5388. doi: 10.1210/en.2009-1168. [PubMed] [Cross Ref]
130. Tagawa N, Sugimoto Y, Yamada J, Kobayashi Y. Strain differences of neurosteroid levels in mouse brain. Steroids. 2006;71(9):776–784. doi: 10.1016/j.steroids.2006.05.008. [PubMed] [Cross Ref]
131. Wahjoepramono EJ, Wijaya LK, Taddei K, Martins G, Howard M, Ruyck Kd, Bates K, Dhaliwald SS, Verdile G, Carruthers M, Martins RN. Distinct effects of testosterone on plasma and cerebrospinal fluid amyloid-beta levels. J Alz Dis. 2008;129:129–137. No doi match found. [PubMed]
132. Ramsden M, Nyborg AC, Murphy MP, Chang L, Stanczyk FZ, Golde TE, Pike CJ. Androgens modulate beta-amyloid levels in male rat brain. J Neurochem. 2003;87(4):1052–5. doi: 10.1046/j.1471-4159.2003.02114.x. [PubMed] [Cross Ref]
133. Rosario ER, Carroll JC, Oddo S, LaFerla FM, Pike CJ. Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer’s disease. J Neurosci. 2006;26(51):13384–13389. doi: 10.1523/JNEUROSCI.2514-06.2006. [PubMed] [Cross Ref]
134. McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada N, Staufenbiel M, Shen Y, Li R. Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J Neurosci. 2010;30(21):7326–7334. doi: 10.1523/JNEUROSCI.1180-10.2010. [PMC free article] [PubMed] [Cross Ref]
135. Rosario ER, Carroll J, Pike CJ. Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways. Brain Res. 2010;1359:281–290. doi: 10.1016/j.brainres.2010.08.068. [PMC free article] [PubMed] [Cross Ref]
136. Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN. The role of beta amyloid in Alzheimer’s disease: still a cause of everything or the only one who got caught? Pharmacol Res. 2004;50:397–409. doi: 10.1016/j.phrs.2003.12.028. [PubMed] [Cross Ref]
137. Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, Haass C. The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid beta Protein. Ann NY Acad Sci. 1996;777:57–64. doi: 10.1111/j.1749-6632.1996.tb34401.x. [PubMed] [Cross Ref]
138. Jaffe A, Toran-Allerand C, Greengard P, Gandy S. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem. 1994;269(18):13065–13068. No doi match found. [PubMed]
139. Chang D, Kwan J, Timiras PS. Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. Adv Exp Med Biol. 1997;429:261–71. No doi match found. [PubMed]
140. Manthey D, Heck S, Engert S, Behl C. Estrogen induces a rapid secretion of amyloid b precursor protein via the mitogen-activated protein kinase pathway. Eur J Biochem. 2001;268(15):4285–4291. doi: 10.1046/j.1432-1327.2001.02346.x. [PubMed] [Cross Ref]
141. Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum J, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4(4):447–451. doi: 10.1038/nm0498-447. [PubMed] [Cross Ref]
142. Vincent B, Smith JD. Effect of estradiol on neuronal Swedish-mutated beta-amyloid precursor protein metabolism: reversal by astrocytic cells. Biochem Biophys Res Commun. 2000;271(1):82–5. doi: 10.1006/bbrc.2000.2581. [PubMed] [Cross Ref]
143. Zhang S, Huang Y, Zhu YC, Yao T. Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway. Acta Pharmacol Sin. 2005;26(2):171–6. doi: 10.1111/j.1745-7254.2005.00538.x. [PubMed] [Cross Ref]
144. Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, Greengard P. Testosterone reduces neuronal secretion of Alzheimer’s b-amyloid peptides. Proc Natl Acad Sci USA. 2000;97(3):1202–1205. doi: 10.1073/pnas.97.3.1202. [PubMed] [Cross Ref]
145. Goodenough S, Engert S, Behl C. Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett. 2000;296(1):49–52. doi: 10.1016/S0304-3940(00)01622-0. [PubMed] [Cross Ref]
146. Zhang S, Huang Y, Zhu Y-c, Yao T. Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway. Acta Pharmacol Sin. 2005;26(2):171–176. doi: 10.1111/j.1745-7254.2005.00538.x. [PubMed] [Cross Ref]
147. Manthey D, Heck S, Behl C. The female sex hormone estrogen induces an increased release of soluble non-amyloidogenic amyloid b precursor protein (sAPP) via the activation of mitogen-activated-protein-kinase (MAPKINASE) and phosphokinase C (PKC) Neurobiol Aging. 2000;21(Supplement 1):114. doi: 10.1016/S0197-4580(00)82311-8. [Cross Ref]
148. Thakur MK, Mani ST. Estradiol regulates APP mRNA alternative splicing in the mice brain cortex. Neurosci Lett. 2005;381(1–2):154–157. doi: 10.1016/j.neulet.2005.02.014. [PubMed] [Cross Ref]
149. Shi J, Panickar KS, Yang S-H, Rabbani O, Day AL, Simpkins JW. Estrogen attenuates over-expression of b-amyloid precursor protein messager RNA in an animal model of focal ischemia. Brain Res. 1998;810(1–2):87–92. doi: 10.1016/S0006-8993(98)00888-9. [PubMed] [Cross Ref]
150. Greenfield JP, Leung LW, Cai D, Kaasik K, Gross RS, Rodriguez_Boulan E, Greengard P, Xu H. Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis. J Biol Chem. 2002;277(14):12128–36. doi: 10.1074/jbc.M110009200. [PubMed] [Cross Ref]
151. Li R, Shen Y, Yang LB, Lue LF, Finch C, Rogers J. Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J Neurochem. 2000;75(4):1447–1454. doi: 10.1046/j.1471-4159.2000.0751447.x. [PubMed] [Cross Ref]
152. Leissring MA. The AbetaCs of Abeta -cleaving proteases. J Biol Chem. 2008;283:29645–29649. doi: 10.1074/jbc.R800022200. [PubMed] [Cross Ref]
153. Wang S, Wang R, Chen L, Bennett DA, Dickson DW, Wang D-S. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer’s brain. J Neurochem. 2010;115(1):47–57. doi: 10.1111/j.1471-4159.2010.06899.x. [PMC free article] [PubMed] [Cross Ref]
154. Tang YP, Haslam SZ, Conrad SE, Sisk CL. Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid β scavenger protein. J Alz Dis. 2004;6(4):413–420. No doi match found. [PubMed]
155. Quintela T, Gonçalves I, Baltazar G, Alves C, Saraiva M, Santos C. 17beta-Estradiol induces transthyretin expression in murine choroid plexus via an oestrogen receptor dependent pathway. Cell Mol Neurobiol. 2009;29(4):475–483. doi: 10.1007/s10571-008-9339-1. [PubMed] [Cross Ref]
156. Zhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RD. 17beta-Estradiol regulates insulin-degrading enzyme expression via an ERbeta/PI3-K pathway in hippocampus. Relevance to Alzheimer’s prevention. Neurobiol Aging. 2010 In Press, Corrected Proof. No doi match found. [PMC free article] [PubMed]
157. Huang J, Guan H, Booze RM, Eckman CB, Hersh LB. Estrogen regulates neprilysin activity in rat brain. Neurosci Lett. 2004;367(1):85–7. doi: 10.1016/j.neulet.2004.05.085. [PubMed] [Cross Ref]
158. Shen R, Sumitomo M, Dai J, Hardy DO, Navarro D, Usmani B, Papandreou CN, Hersh LB, Shipp MA, Freedman LP, Nanus DM. Identification and characterization of two androgen response regions in the human neutral endopeptidase gene. Mol Cell Endocrinol. 2000;170(1–2):131–42. doi: 10.1016/S0303-7207(00)00326-9. [PubMed] [Cross Ref]
159. Xiao Z-M, Sun L, Liu Y-M, Zhang J-J, Huang J. Estrogen Regulation of the Neprilysin Gene Through A Hormone-Responsive Element. J Mol Neurosci. 2009;39(1–2):22–6. doi: 10.1007/s12031-008-9168-1. [PubMed] [Cross Ref]
160. Yao M, Nguyen TV, Rosario ER, Ramsden M, Pike CJ. Androgens regulate neprilysin expression: role in reducing beta-amyloid levels. J Neurochem. 2008;105(6):2477–88. doi: 10.1111/j.1471-4159.2008.05341.x. [PubMed] [Cross Ref]
161. Dai D, Wolf DM, Litman ES, White MJ, Leslie KK. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res. 2002;62(3):881–6. No doi match found. [PubMed]
162. Davies S, Dai D, Wolf DM, Leslie KK. Immunomodulatory and transcriptional effects of progesterone through progesterone A and B receptors in Hec50co poorly differentiated endometrial cancer cells. J Soc Gynecol Investig. 2004;11(7):494–9. doi: 10.1016/j.jsgi.2004.04.003. [PubMed] [Cross Ref]
163. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85(2):304–13. doi: 10.1016/0029-7844. [PubMed] [Cross Ref]
164. Persson I, Adami HO, Bergkvist L, Lindgren A, Pettersson B, Hoover R, Schairer C. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Brit Med J. 1989;298(6667):147–51. doi: 10.1136/bmj.298.6667.147. [PMC free article] [PubMed] [Cross Ref]
165. Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J. Progesterone receptors: form and function in brain. Front Neuroendocrinol. 2008;29(2):313–39. No doi match found. [PMC free article] [PubMed]
166. Schumacher M, Guennoun R, Stein DG, De Nicola AF. Progesterone. Therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther. 2007;116(1):77–106. doi: 10.1016/j.pharmthera.2007.06.001. [PubMed] [Cross Ref]
167. Chesler EJ, Juraska JM. Acute administration of estrogen and progesterone impairs the acquisition of the spatial Morris Water Maze in ovariectomized rats. Horm Behav. 2000;38(4):234–242. doi: 10.1006/hbeh.2000.1626. [PubMed] [Cross Ref]
168. Bimonte-Nelson HA, Francis KR, Umphlet CD, Granholm AC. Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats. Eur J Neurosci. 2006;24(1):229–42. doi: 10.1111/j.1460-9568.2006.04867.x. [PubMed] [Cross Ref]
169. Díaz-Véliz G, Urresta F, Dussaubat N, Mora S. Progesterone effects on the acquisition of conditioned avoidance responses and other motoric behaviors in intact and ovariectomized rats. Psychoneuroendocrinology. 1994;19(4):387–394. doi: 10.1016/0306-4530(94)90018-3. [PubMed] [Cross Ref]
170. Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memorytask by ovariectomized aged rats. Neurobiol Aging. 2000;21(1):107–116. doi: 10.1016/S0197-4580(00)00103-2. [PubMed] [Cross Ref]
171. Rice MM, Graves AB, McCurry SM, Gibbons LE, Bowen JD, McCormick WC, Larson EB. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women. The Kame Project. Arch Intern Med. 2000;160(11):1641–1649. doi: 10.1001/archinte.160.11.1641. [PubMed] [Cross Ref]
172. Rosario ER, Ramsden M, Pike CJ. Progestins inhibit the neuroprotective effects of estrogen in rat hippocampus. Brain Res. 2006;1099(1):206–210. doi: 10.1016/j.brainres.2006.03.127. [PubMed] [Cross Ref]
173. Carroll JC, Rosario ER, Pike CJ. Progesterone blocks estrogen neuroprotection from kainate in middle-aged female rats. Neurosci Lett. 2008;445(3):229–232. doi: 10.1016/j.neulet.2008.09.010. [PMC free article] [PubMed] [Cross Ref]
174. Ciriza I, Azcoitia I, Garcia-Segura LM. Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo. J Neuroendocrinol. 2004;16(1):58–63. doi: 10.1111/j.1365-2826.2004.01121.x. [PubMed] [Cross Ref]
175. Ciriza I, Carrero P, Frye CA, Garcia-Segura LM. Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective. J Neurobiol. 2006;66(9):916–28. doi: 10.1002/neu.20293. [PubMed] [Cross Ref]
176. Frye CA, Walf A. Progesterone, administered before kainic acid, prevents decrements in cognitive performance in the Morris Water Maze. Developmental Neurobiology. 2011;71(2):142–152. doi: 10.1002/dneu.20832. [PMC free article] [PubMed] [Cross Ref]
177. Bimonte-Nelson HA, Nelson ME, Granholm AC. Progesterone counteracts estrogen-induced increases in neurotrophins in the aged female rat brain. Neuroreport. 2004;15(17):2659–63. doi: 10.1097/00001756-200412030-00021. [PubMed] [Cross Ref]
178. Irwin RW, Yao J, Hamilton RT, Cadenas E, Brinton RD, Nilsen J. Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Endocrinology. 2008;149(6):3167–75. doi: 10.1210/en.2007-1227. [PubMed] [Cross Ref]
179. Garcia-Segura LM, Cardona-Gomez P, Naftolin F, Chowen JA. Estradiol upregulates Bcl-2 expression in adult brain neurons. Neuroreport. 1998;9(4):593–7. doi: 10.1097/00001756-199803090-00006. [PubMed] [Cross Ref]
180. Nilsen J, Brinton RD. Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143(1):205–212. doi: 10.1210/en.143.1.205. [PubMed] [Cross Ref]
181. Woolley CS, McEwen BS. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol. 1993;336(2):293–306. doi: 10.1002/cne.903360210. [PubMed] [Cross Ref]
182. Azcoitia I, Fernandez-Galaz MC, Sierra A, Garcia-Segura LM. Gonadal hormones affect neuronal vulnerability to excitotoxin-induced degeneration. J Neurocytol. 1999;28:699–710. doi: 10.1023/A:1007025219044. [PubMed] [Cross Ref]
183. Toung TJ, Chen TY, Littleton-Kearney MT, Hurn PD, Murphy TJ. Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats. J Cereb Blood Flow Metab. 2004;24(10):1160–1166. doi: 10.1097/01.WCB.0000135594.13576.D2. [PubMed] [Cross Ref]
184. Gibbs RB. Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function. Neuroscience. 2000;101(4):931–8. doi: 10.1016/S0306-4522(00)00433-4. [PubMed] [Cross Ref]
185. Carroll JC, Rosario ER, Villamagna A, Pike CJ. Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xtransgenic-Alzheimer’s disease mice. Endocrinology. 2010;151(6):2713–2722. doi: 10.1210/en.2009-1487. [PubMed] [Cross Ref]
186. Henderson VW. Estrogens, Episodic Memory, and Alzheimer’s Disease. A Critical Update. Semin Reprod Med. 2009;27(03):283, 293. No doi match found. [PubMed]
187. Miller V, Black D, Brinton E, Budoff M, Cedars M, Hodis H, Lobo R, Manson J, Merriam G, Naftolin F, Santoro N, Taylor H, Harman S. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) J Cardiovasc Trans Res. 2009;2(3):228–239. doi: 10.1007/s12265-009-9104-y. [PMC free article] [PubMed] [Cross Ref]
188. Clark JH, Hsueh AJW, Peck EJ., Jr regulation of estrogen receptor replenishment by progesterone. Ann NY Acad Sci. 1977;286:161–179. doi: 10.1111/j.1749-6632.1977.tb29414.x. [PubMed] [Cross Ref]
189. Leavitt WW, Chen TJ, Allen TC. Regulation of progesterone receptor formation by estrogen action. Ann N Y Acad Sci. 1977;286:210–25. doi: 10.1111/j.1749-6632.1977.tb29418.x. [PubMed] [Cross Ref]
190. Jayaraman A, Pike CJ. Progesterone attenuates oestrogen neuroprotection via downregulation of oestrogen receptor expression in cultured neurones. J Neuroendocrinol. 2009;21(1):77–81. doi: 10.1111/j.1365-2826.2008.01801.x. [PMC free article] [PubMed] [Cross Ref]
191. Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta. J Neurochem. 2010;115(5):1277–87. doi: 10.1111/j.1471-4159.2010.07038.x. [PMC free article] [PubMed] [Cross Ref]
192. Biegon A, Parsons B, Krey LC, Kamel F, McEwen BS. Behavioral and neuroendocrine effects of long-term progesterone treatment in the rat. Neuroendocrinology. 1983;37(5):332–5. doi: 10.1159/000123571. [PubMed] [Cross Ref]
193. Brown TJ, MacLusky NJ. Progesterone modulation of estrogen receptors in microdissected regions of the rat hypothalamus. Mol Cell Neurosci. 1994;5(3):283–90. doi: 10.1006/mcne.1994.1033. [PubMed] [Cross Ref]
194. DonCarlos LL, Malik K, Morrell JI. Region-specific effects of ovarian hormones on estrogen receptor immunoreactivity. Neuroreport. 1995;6(15):2054–8. doi: 10.1097/00001756-199510010-00024. [PubMed] [Cross Ref]
195. Gasc JM, Baulieu EE. Regulation by estradiol of the progesterone receptor in the hypothalamus and pituitary: an immunohistochemical study in the chicken. Endocrinology. 1988;122(4):1357–65. doi: 10.1210/endo-122-4-1357. [PubMed] [Cross Ref]
196. Godwin J, Hartman V, Grammer M, Crews D. Progesterone inhibits female-typical receptive behavior and decreases hypothalamic estrogen and progesterone receptor messenger ribonucleic acid levels in whiptail lizards (genus Cnemidophorus) Horm Behav. 1996;30(2):138–44. doi: 10.1006/hbeh.1996.0017. [PubMed] [Cross Ref]
197. Thrower S, Lim L. The nuclear oestrogen receptor in the female rat. Effects of oestradiol administration during the oestrous cycle on the uterus and contrasting effects of progesterone on the uterus and hypothalamus. Biochem J. 1981;198(2):385–9. No doi match found. [PubMed]
198. Doraiswamy PM, Bieber F, Kaiser L, Krishnan KR, Reuning-Scherer J, Gulanski B. The Alzheimer’s disease assessment scale. Patterns and predictors of baseline cognitive performance in multicenter Alzheimer’s disease trials. Neurology. 1997;48(6):1511–1517. No doi match found. [PubMed]
199. Henderson VW, Watt L, Galen Buckwalter J. Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology. 1996;21(4):421–430. doi: 10.1016/0306-4530(95)00060-7. [PubMed] [Cross Ref]
200. Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR. High-dose estradiol improves cognition for women with AD - Results of a randomized study. Neurology. 2001;57(4):605–612. No doi match found. [PubMed]
201. Fillit H, Weinreb H, Cholst I, Luine V, McEwen B, Amador R, Zabriskie J. Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology. 1986;11(3):337–45. doi: 10.1016/0306-4530(86)90019-3. [PubMed] [Cross Ref]
202. Henderson VW, Paganini_Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow MR. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54(2):295–301. No doi match found. [PubMed]
203. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. A randomized controlled trial. J Am Med Assoc. 2000;283(8):1007. doi: 10.1001/jama.283.8.1007. [PubMed] [Cross Ref]
204. Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC. Effects of estrogen on cognition, mood, and cerebral blood flow in AD. A controlled study. Neurology. 2000;54(11):2061–2066. No doi match found. [PubMed]
205. Rigaud AS, Andre G, Vellas B, Touchon J, Pere JJ. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology. 2003;60:148–149. No doi match found. [PubMed]
206. Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Donnell Lingle D, Metter E. 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. No doi match found. [PubMed]
207. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol. 1994;140(3):256–261. No doi match found. [PubMed]
208. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol. 1994;51(9):896–900. No doi match found. [PubMed]
209. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Int Med. 1996;156(19):2213–2217. doi: 10.1001/archinte.156.19.2213. [PubMed] [Cross Ref]
210. Tang MX, Jacobs D, Stern Y, Marder K, Schofield PR, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet. 1996;348(9025):429. doi: 10.1016/S0140-6736(96)03356-9. [PubMed] [Cross Ref]
211. 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):965–70. No doi match found. [PubMed]
212. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JCS. Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women. The Cache County Study. J Am Med Assoc. 2002;288(17):2123–2129. doi: 10.1001/jama.288.17.2123. [PubMed] [Cross Ref]
213. Baldereschi M, Di Carlo A, Lepore V, Bracco L, Maggi S, Grigoletto F, Scarlato G, Amaducci L. Estrogen-replacement therapy and Alzheimer’s disease in the Italian Longitudinal Study on Aging. Neurology. 1998;50(4):996–1002. No doi match found. [PubMed]
214. Brenner D, Kukull W, Stergachis A, van Belle G, Bowen J, McCormick W, Teri L, Larson E. Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study. Am J Epidemiol. 1994;140(3):262–267. No doi match found. [PubMed]
215. Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76(1):103–5. doi: 10.1136/jnnp.2003.024927. [PMC free article] [PubMed] [Cross Ref]
216. Slooter AJC, Bronzova J, Witteman JCM, Broeckhoven CV, Hofman A, Duijn CMv. Estrogen use and early onset alzheimer’s disease: a population-based study. J Neurol Neurosurg Psychiatry. 1999;67:779–781. doi: 10.1136/jnnp.67.6.779. [PMC free article] [PubMed] [Cross Ref]
217. Haskell SG, Richardson ED, Horwitz RI. The effect of estrogen replacement therapy on cognitive function in women. A critical review of the literature. J Clin Epidemiol. 1997;50(11):1249–1264. doi: 10.1016/S0895-4356(97)00169-8. [PubMed] [Cross Ref]
218. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience. 2000;101(3):485–512. doi: 10.1016/S0306-4522(00)00410-3. [PubMed] [Cross Ref]
219. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. J Am Med Assoc. 1998;279(9):688–695. doi: 10.1001/jama.279.9.688. [PubMed] [Cross Ref]
220. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J. Conjugated equine estrogens and global cognitive function in postmenopausal women. Women’s Health Initiative Memory Study. J Am Med Assoc. 2004;291(24):2959–2968. doi: 10.1001/jama.291.24.2959. [PubMed] [Cross Ref]
221. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. Women’s Health Initiative Memory Study. J Am Med Assoc. 2004;291(24):2947–58. doi: 10.1001/jama.291.24.2947. [PubMed] [Cross Ref]
222. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J. 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. J Am Med Assoc. 2003;289(20):2651. doi: 10.1001/jama.289.20.2651. [PubMed] [Cross Ref]
223. Henderson VW. Estrogen-containing hormone therapy and Alzheimer’s disease risk. Understanding discrepant inferences from observational and experimental research. Neuroscience. 2006;138(3):1031–1039. doi: 10.1016/j.neuroscience.2005.06.017. [PubMed] [Cross Ref]
224. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. J Am Med Assoc. 2002;288(17):2170–2. doi: 10.1001/jama.288.17.2170. [PubMed] [Cross Ref]
225. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia. The critical window theory revisited. Ann Neurol. 2010 No doi match found. [PMC free article] [PubMed]
226. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–2559. doi: 10.1210/jc.2009-2354. [PubMed] [Cross Ref]
227. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001;57(1):80–8. No doi match found. [PubMed]
228. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2005;63(2):177–85. doi: 10.1001/archneur.63.2.nct50002. [PubMed] [Cross Ref]
229. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male. 2003;6(1):13. No doi match found. [PubMed]
230. Bachmann GA. Androgen cotherapy in menopause. Evolving benefits and challenges. Am J Obstet Gynecol. 1999;180(3 Supplement 1):S308–S311. doi: 10.1016/S0002-9378(99)70724-6. [PubMed] [Cross Ref]
231. Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. J Am Med Assoc. 2001;285(22):2891–2897. doi: 10.1001/jama.285.22.2891. [PubMed] [Cross Ref]
232. Herrington DM, Espeland MA, Crouse JR, III, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol. 2001;21(12):1955–1961. doi: 10.1161/hq1201.100241. [PubMed] [Cross Ref]
233. Bake S, Sohrabji F. 17beta-estradiol differentially regulates blood-brain barrier permeability in young and aging female rats. Endocrinology. 2004;145(12):5471–5. doi: 10.1210/en.2004-0984. [PubMed] [Cross Ref]
234. Miranda P, Williams CL, Einstein G. Granule cells in aging rats are sexually dimorphic in their response to estradiol. J Neurosci. 1999;19(9):3316–3325. No doi match found. [PubMed]
235. Adams MM, Shah RA, Janssen WGM, Morrison JH. Different modes of hippocampal plasticity in response to estrogen in young and aged female rats. Proc Natl Acad Sci USA. 2001;98(14):8071–8076. doi: 10.1073/pnas.141215898. [PubMed] [Cross Ref]
236. Jezierski MK, Sohrabji F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol Aging. 2001;22(2):309–319. doi: 10.1016/S0197-4580(00)00230-X. [PubMed] [Cross Ref]
237. Savonenko AV, Markowska AL. The cognitive effects of ovariectomy and estrogen replacement are modulated by aging. Neuroscience. 2003;119(3):821–830. doi: 10.1016/S0306-4522(03)00213-6. [PubMed] [Cross Ref]
238. Talboom JS, Williams BJ, Baxley ER, West SG, Bimonte-Nelson HA. Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats. Neurobiol Learn Mem. 2008;90(1):155–163. doi: 10.1016/j.nlm.2008.04.002. [PMC free article] [PubMed] [Cross Ref]
239. Singer CA, McMillan PJ, Dobie DJ, Dorsa DM. Effects of estrogen replacement on choline acetyltransferase and trkA mRNA expression in the basal forebrain of aged rats. Brain Res. 1998;789(2):343–346. doi: 10.1016/S0006-8993(98)00142-5. [PubMed] [Cross Ref]
240. Aenlle KK, Kumar A, Cui L, Jackson TC, Foster TC. Estrogen effects on cognition and hippocampal transcription in middle-aged mice. Neurobiol Aging. 2009;30(6):932–945. doi: 10.1016/j.neurobiolaging.2007.09.004. [PMC free article] [PubMed] [Cross Ref]
241. Stone DJ, Rozovsky I, Morgan TE, Anderson CP, Lopez LM, Shick J, Finch CE. Effects of Age on Gene Expression during Estrogen-Induced Synaptic Sprouting in the Female Rat. Exp Neurol. 2000;165(1):46–57. doi: 10.1006/exnr.2000.7455. [PubMed] [Cross Ref]
242. Nordell VL, Scarborough MM, Buchanan AK, Sohrabji F. Differential effects of estrogen in the injured forebrain of young adult and reproductive senescent animals. Neurobiol Aging. 2003;24(5):733–743. doi: 10.1016/S0197-4580(02)00193-8. [PubMed] [Cross Ref]
243. Johnson AB, Bake S, Lewis DK, Sohrabji F. Temporal expression of IL-1beta protein and mRNA in the brain after systemic LPS injection is affected by age and estrogen. J Neuroimmunol. 2006;174(1–2):82–91. doi: 10.1016/j.jneuroim.2006.01.019. [PubMed] [Cross Ref]
244. Selvamani A, Sohrabji F. Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol Aging. 2010;31(9):1618–1628. doi: 10.1016/j.neurobiolaging.2008.08.014. [PMC free article] [PubMed] [Cross Ref]
245. Dubal DB, Wise PM. Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology. 2001;142(1):43–8. doi: 10.1210/en.142.1.43. [PubMed] [Cross Ref]
246. Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke. 2000;31(1):161–8. No doi match found. [PubMed]
247. Rubin BS, Fox TO, Bridges RS. Estrogen binding in nuclear and cytosolic extracts from brain and pituitary of middle-aged female rats. Brain Res. 1986;383(1–2):60–7. doi: 10.1016/0006-8993(86)90008-9. [PubMed] [Cross Ref]
248. Wise PM, Parsons B. Nuclear estradiol and cytosol progestin receptor concentrations in the brain and the pituitary gland and sexual behavior in ovariectomized estradiol-treated middle-aged rats. Endocrinology. 1984;115(2):810–6. doi: 10.1210/endo-115-2-810. [PubMed] [Cross Ref]
249. Waters EM, Yildirim M, Janssen WGM, Lou WYW, McEwen BS, Morrison JH, Milner TA. Estrogen and aging affect the synaptic distribution of estrogen receptor beta-immunoreactivity in the CA1 region of female rat hippocampus. Brain Res. 2011;1379:86–97. doi: 10.1016/j.brainres.2010.09.069. [PMC free article] [PubMed] [Cross Ref]
250. Mehra RD, Sharma K, Nyakas C, Vij U. Estrogen receptor alpha and beta immunoreactive neurons in normal adult and aged female rat hippocampus. A qualitative and quantitative study. Brain Res. 2005;1056(1):22–35. doi: 10.1016/j.brainres.2005.06.073. [PubMed] [Cross Ref]
251. Sharma PK, Thakur MK. Expression of estrogen receptor (ER) alpha and beta in mouse cerebral cortex. Effect of age, sex and gonadal steroids. Neurobiol Aging. 2006;27(6):880–887. doi: 10.1016/j.neurobiolaging.2005.04.003. [PubMed] [Cross Ref]
252. Thakur MK, Sharma PK. Transcription of estrogen receptor alpha and beta in mouse cerebral cortex. Effect of age, sex, 17beta-estradiol and testosterone. Neurochem Int. 2007;50(2):314–321. doi: 10.1016/j.neuint.2006.08.019. [PubMed] [Cross Ref]
253. Adams MM, Fink SE, Shah RA, Janssen WGM, Hayashi S, Milner TA, McEwen BS, Morrison JH. Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J Neurosci. 2002;22(9):3608–3614. No doi match found. [PubMed]
254. Ishunina TA, Fischer DF, Swaab DF. Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s disease. Neurobiol Aging. 2007;28(11):1670–1681. doi: 10.1016/j.neurobiolaging.2006.07.024. [PubMed] [Cross Ref]
255. Daniel JM, Hulst JL, Berbling JL. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2006;147(1):607–14. doi: 10.1210/en.2005-0998. [PubMed] [Cross Ref]
256. Silva I, Mello LEAM, Freymüller E, Haidar MA, Baracat EC. Onset of estrogen replacement has a critical effect on synaptic density of CA1 hippocampus in ovariectomized adult rats. Menopause. 2003;10(5):406–411. doi: 10.1097/01.GME.0000064816.74043.E9. [PubMed] [Cross Ref]
257. Bohacek J, Bearl AM, Daniel JM. Long-term ovarian hormone deprivation alters the ability of subsequent oestradiol replacement to regulate choline acetyltransferase protein levels in the hippocampus and prefrontal cortex of middle-aged rats. J Neuroendocrinol. 2008;20(8):1023–7. doi: 10.1111/j.1365-2826.2008.01752.x. [PubMed] [Cross Ref]
258. Bohacek J, Daniel JM. The ability of oestradiol administration to regulate protein levels of oestrogen receptor alpha in the hippocampus and prefrontal cortex of middle-aged rats is altered following long-term ovarian hormone deprivation. J Neuroendocrinol. 2009;21(7):640–647. doi: 10.1111/j.1365-2826.2009.01882.x. [PubMed] [Cross Ref]
259. Wu D, Gore AC. Changes in androgen receptor, estrogen receptor alpha, and sexual behavior with aging and testosterone in male rats. Horm Behav. 2010;58(2):306–316. doi: 10.1016/j.yhbeh.2010.03.001. [PMC free article] [PubMed] [Cross Ref]
260. Chambers KC, Phoenix CH. Testosterone and the decline of sexual behavior in aging male rats. Behav Neural Biol. 1984;40(1):87–97. doi: 10.1016/S0163-1047(84)90194-8. [PubMed] [Cross Ref]
261. Yoshikazu S, Akihiko S, Hideki A, Ryu-Ichi K, Hiroki H, Taiji T. Restoration of sexual behavior and dopaminergic neurotransmission by long term exogenous testosterone replacement in aged male rats. J Urol. 1998;160(4):1572–1575. doi: 10.1016/S0022-5347(01)62615-6. [PubMed] [Cross Ref]
262. Chambers KC, Thornton JE, Roselli CE. Age-related deficits in brain androgen binding and metabolism, testosterone, and sexual behavior of male rats. Neurobiol Aging. 1991;12(2):123–130. doi: 10.1016/0197-4580(91)90050-T. [PubMed] [Cross Ref]
263. Tohgi H, Utsugisawa K, Yamagata M, Yoshimura M. Effects of age on messenger RNA expression of glucocorticoid, thyroid hormone, androgen, and estrogen receptors in postmortem human hippocampus. Brain Res. 1995;700(1–2):245–253. doi: 10.1016/0006-8993(95)00971-R. [PubMed] [Cross Ref]
264. Wu D, Lin G, Gore AC. Age-related changes in hypothalamic androgen receptor and estrogen receptor α in male rats. J Comp Neurol. 2009;512(5):688–701. doi: 10.1002/cne.21925. [PMC free article] [PubMed] [Cross Ref]
265. Sato Y, Shibuya A, Adachi H, Kato R, Horita H, Tsukamoto T. Restoration of sexual behavior and dopaminergic neurotransmission by long term exogenous testosterone replacement in aged male rats. J Urol. 1998;160(4):1572–5. doi: 10.1016/S0022-5347(01)62615-6. [PubMed] [Cross Ref]
266. Putnam SK, Du J, Sato S, Hull EM. Testosterone restoration of copulatory behavior correlates with medial preoptic dopamine release in castrated male rats. Horm Behav. 2001;39(3):216–24. doi: 10.1006/hbeh.2001.1648. [PubMed] [Cross Ref]
267. Fargo KN, Iwema CL, Clark-Phelps MC, Sengelaub DR. Exogenous testosterone reverses age-related atrophy in a spinal neuromuscular system. Horm Behav. 2007;51(1):20–30. doi: 10.1016/j.yhbeh.2006.07.006. [PubMed] [Cross Ref]
268. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J Am Med Assoc. 2002;288(3):321–333. doi: 10.1001/jama.288.3.321. [PubMed] [Cross Ref]
269. Brinton RD. Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM. J Alz Dis. 2004;6(6 Suppl):S27–35. No doi match found. [PubMed]
270. Bryant HU, Dere WH. Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med. 1998;217(1):45–52. No doi match found. [PubMed]
271. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337(23):1641–7. doi: 10.1056/NEJM199712043372301. [PubMed] [Cross Ref]
272. Baker VL, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe RB. Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab. 1998;83(1):6–13. doi: 10.1210/jc.83.1.6. [PubMed] [Cross Ref]
273. O’Neill K, Chen S, Brinton RD. Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer’s disease. Exp Neurol. 2004;185(1):63–80. doi: 10.1016/j.expneurol.2003.09.005. [PubMed] [Cross Ref]
274. Nilsen J, Mor G, Naftolin F. Raloxifene induces neurite outgrowth in estrogen receptor positive PC12 cells. Menopause. 1998;5(4):211–6. doi: 10.1097/00042192-199805040-00005. [PubMed] [Cross Ref]
275. Grandbois M, Morissette M, Callier S, Di Paolo T. Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice. Neuroreport. 2000;11(02):343–346. doi: 10.1097/00001756-200002070-00024. [PubMed] [Cross Ref]
276. Zhang L, Rubinow DR, Xaing G-q, Li B-S, Chang YH, Maric D, Barker JL, Ma W. Estrogen protects against beta-amyloid-induced neurotoxicity in rat hippocampal neurons by activation of Akt. Neuroreport. 2001;12(9):1919–1923. doi: 10.1097/00001756-200107030-00030. [PubMed] [Cross Ref]
277. Chae HS, Bach JH, Lee MW, Kim HS, Kim YS, Kim KY, Choo KY, Choi SH, Park CH, Lee SH, Suh YH, Kim SS, Lee WB. Estrogen attenuates cell death induced by carboxy-terminal fragment of amyloid precursor protein in PC12 through a receptor-dependent pathway. J Neurosci Res. 2001;65(5):403–7. doi: 10.1002/jnr.1167. [PubMed] [Cross Ref]
278. Nickelsen T, Lufkin EG, Riggs BL, Cox DA, Crook TH. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology. 1999;24(1):115–128. doi: 10.1016/S0306-4530(98)00041-9. [PubMed] [Cross Ref]
279. Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005;162(4):683–690. doi: 10.1176/appi.ajp.162.4.683. [PubMed] [Cross Ref]
280. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc. 1998;279(18):1445–1451. doi: 10.1001/jama.279.18.1445. [PubMed] [Cross Ref]
281. Cohen FJ, Lu Y. Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials. Maturitas. 2000;34(1):65–73. doi: 10.1016/S0378-5122(99)00090-0. [PubMed] [Cross Ref]
282. Breuer B, Anderson R. The relationship of tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents. Women Health. 2000;31(1):71–85. doi: 10.1300/J013v31n01_05. [PubMed] [Cross Ref]
283. Ernst T, Chang L, Cooray D, Salvador C, Jovicich J, Walot I, Boone K, Chlebowski R. The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst. 2002;94(8):592–597. No doi match found. [PubMed]
284. Paganini-Hill A, Clark LJ. Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat. 2000;64(2):165–76. doi: 10.1023/A:1006426132338. [PubMed] [Cross Ref]
285. Shilling V, Jenkins V, Fallowfield L, Howell T. The effects of hormone therapy on cognition in breast cancer. J Steroid Biochem Mol Biol. 2003;86(3–5):405–12. doi: 10.1016/j.jsbmb.2003.07.001. [PubMed] [Cross Ref]
286. Stauffer SR, Coletta CJ, Tedesco R, Nishiguchi G, Carlson K, Sun J, Katzenellenbogen BS, Katzenellenbogen JA. Pyrazole ligands: structure affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem. 2000;43(26):4934–4947. doi: 10.1021/jm000170m. [PubMed] [Cross Ref]
287. Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: structure activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem. 2001;44(24):4230–4251. doi: 10.1021/jm010254a. [PubMed] [Cross Ref]
288. Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997;388(4):507–525. doi: 10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6. [PubMed] [Cross Ref]
289. Zhao L, O’Neill K, Diaz Brinton R. Selective estrogen receptor modulators (SERMs) for the brain. Current status and remaining challenges for developing NeuroSERMs. Brain Res Rev. 2005;49(3):472–493. doi: 10.1016/j.brainresrev.2005.01.009. [PubMed] [Cross Ref]
290. Jelks KB, Wylie R, Floyd CL, McAllister AK, Wise P. Estradiol Targets Synaptic Proteins to Induce Glutamatergic Synapse Formation in Cultured Hippocampal Neurons. Critical Role of Estrogen Receptor-alpha. J Neurosci. 2007;27(26):6903–6913. doi: 10.1523/JNEUROSCI.0909-07.2007. [PubMed] [Cross Ref]
291. Zhao L, Wu T-w, Brinton RD. Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons. Brain Res. 2004;1010(1–2):22–34. doi: 10.1016/j.brainres.2004.02.066. [PubMed] [Cross Ref]
292. Cordey M, Pike CJ. Neuroprotective properties of selective estrogen receptor agonists in cultured neurons. Brain Res. 2005;1045(1–2):217–23. No doi match found. [PubMed]
293. Miller NR, Jover T, Cohen HW, Zukin RS, Etgen AM. Estrogen can act via estrogen receptor alpha and beta to protect hippocampal neurons against global ischemia-induced cell death. Endocrinology. 2005;146(7):3070–3079. doi: 10.1210/en.2004-1515. [PubMed] [Cross Ref]
294. Dai X, Chen L, Sokabe M. Neurosteroid estradiol rescues ischemia-induced deficit in the long-term potentiation of rat hippocampal CA1 neurons. Neuropharmacol. 2007;52(4):1124–1138. doi: 10.1016/j.neuropharm.2006.11.012. [PubMed] [Cross Ref]
295. Carswell HVO, Macrae IM, Gallagher L, Harrop E, Horsburgh KJ. Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia. Am J Physiol Heart Circ Physiol. 2004;287(4):H1501–1504. doi: 10.1152/ajpheart.00227.2004. [PubMed] [Cross Ref]
296. Brown TR. Nonsteroidal selective androgen receptors modulators (SARMs) : designer androgens with flexible structures provide clinical promise. Endocrinology. 2004;145(12):5417–9. doi: 10.1210/en.2004-1207. [PubMed] [Cross Ref]
297. Wilson EM. Muscle-bound? A tissue-selective nonsteroidal androgen receptor modulator. Endocrinology. 2007;148(1):1–3. doi: 10.1210/en.2006-1368. [PubMed] [Cross Ref]
298. Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, Dalton JT. Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinology. 2005;146(11):4887–97. doi: 10.1210/en.2005-0572. [PMC free article] [PubMed] [Cross Ref]
299. Li JJ, Sutton JC, Nirschl A, Zou Y, Wang H, Sun C, Pi Z, Johnson R, Krystek SR, Jr, Seethala R, Golla R, Sleph PG, Beehler BC, Grover GJ, Fura A, Vyas VP, Li CY, Gougoutas JZ, Galella MA, Zahler R, Ostrowski J, Hamann LG. Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications. J Med Chem. 2007;50(13):3015–3025. doi: 10.1021/jm070312d. [PubMed] [Cross Ref]
300. Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR, Jr, Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG. Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocrinology. 2007;148(1):4–12. doi: 10.1210/en.2006-0843. [PubMed] [Cross Ref]
301. Gao W, Dalton JT. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs) Drug Disc Today. 2007;12(5–6):241–248. doi: 10.1016/j.drudis.2007.01.003. [PMC free article] [PubMed] [Cross Ref]
302. Gao W, Dalton JT. Ockham’s razor and Selective Androgen Receptor Modulators (SARMs): are we overlooking the role of 5alpha-reductase? Mol Intervent. 2007;7:10–13. doi: 10.1124/mi.7.1.3. [PMC free article] [PubMed] [Cross Ref]