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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1099-1103
Copyright © 2001 by The Endocrine Society

Original Studies

Endogenous Sex Hormone Levels in Postmenopausal Women with Alzheimer’s Disease

C. J. Cunningham, M. Sinnott, A. Denihan, M. Rowan, J. B. Walsh, R. O’Moore, D. Coakley, R. F. Coen, B. A. Lawler and D. D. O’Neill

Mercer’s Institute for Research in Aging (C.J.C., A.D., J.B.W., R.O., D.C., R.F.C., B.A.L., D.D.O.) and Central Pathology Laboratory (M.S.), St. James’ Hospital, Dublin 8; and Department of Clinical Pharmacology (M.R.), Trinity College, Dublin, Ireland

Address all correspondence and requests for reprints to: Dr. C. J. Cunningham, Mercer’s Institute for Research in Aging, St. James’ Hospital, Dublin 8, Ireland. E-mail: ccunningham{at}stjames.ie


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A cross-sectional study examined whether there was a difference in endogenous serum sex hormone levels between community-dwelling postmenopausal women with Alzheimer’s disease (AD) and healthy controls. Total morning levels of serum estrone, estradiol, androstenedione, testosterone, and cortisol were measured in 52 nondepressed women with AD and 60 postmenopausal women who were neither depressed nor cognitively impaired. Estradiol was undetectable in 35.7% of cases, but detectable hormone was found in 96–100% of cases otherwise. After adjustment for potential confounds, serum levels were significantly higher for estrone (P = 0.0057) and androstenedione (P = 0.02), but not testosterone (P = 0.086) or estradiol (P = 0.59), in subjects with AD. Sex hormone levels did not correlate with cognitive scores in either group. Although the failure to detect estradiol in a third of cases limits the conclusions that can be drawn for this hormone, the possibility that AD is associated with abnormalities in certain serum sex hormone levels should be considered and warrants further research.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENT OBSERVATIONAL studies have suggested that users of estrogen replacement therapy are less likely to develop Alzheimer’s disease (AD) (1, 2, 3). This association remained after adjusting for age and education. However, several other studies have found no such association (4, 5), and more recently, two randomized controlled trials have found no benefit from estrogen replacement therapy (6, 7), calling its therapeutic benefit into question. These recent trials looked at the administration of estrogen over fairly short periods (<1 yr), so the generalizability to more chronic exposure is unclear. Estrogen is still detectable, albeit reduced, after the menopause and varies considerably between individuals (8). There is some evidence that serum levels remain similar in a given individual for several years (9, 10). Examining the association between postmenopausal serum estrogen levels and a given biological effect may therefore allow the study of more chronic estrogenic effects in elderly women.

Cross-sectional studies can only allow estimation of the risk of developing AD if the risk factor in question remains stable before and after a person develops the disease (specifically, in this case, if serum estrogen levels are unaltered by developing AD). This may not be the case. Postmenopausal women with acute illnesses (11) and insulin-dependent diabetes (12) have been shown to have higher serum estrogen levels. Given that circulating estrogen is formed postmenopausally by metabolism of adrenal and gonadal steroids (8) and that AD is associated with a disorder of the hypothalamic-pituitary-adrenal (HPA) axis (13, 14, 15, 16, 17, 18), the possibility that AD might be associated with an alteration in estrogen production must also be considered.

Our objective was to determine whether total serum levels of the two estrogen subtypes (estrone and estradiol) or their precursors (androstenedione and testosterone) were altered in Alzheimer’s disease, having controlled for all relevant confounding factors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Community-dwelling postmenopausal women were recruited between April 1997 and April 1998. Subjects who were taking estrogen preparations (oral, parenteral, or topical) or corticosteroids or had done so in the preceding 6 months were excluded. Subjects with acute illnesses (including upper respiratory tract infections) at or within 1 week of assessment or who had previous ovariectomy [because of a known association with lower levels of serum androgens (19)] or with depression [DSM IV (20) criteria] were also excluded. Women taking antidepressant medications who were not currently depressed were included. Depressed subjects were excluded so as to separate, as far as possible, potential estrogenic effects on cognition and mood.

Cases (52 subjects) were consecutive referrals to an out-patient memory clinic who met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (21) and Diagnostic and Statistical Manual of Mental Disorders (20) criteria for probable Alzheimer’s disease. Detailed neuropsychological testing and neuroimaging were used to establish diagnosis in all cases (22). Patients with severe dementia [Mini Mental State Examination (23) (MMSE) score of 14 or less] were excluded because of the difficulty in excluding depression in these circumstances.

All subjects (cases and controls) were administered the 30-item Geriatric Depression Scale (24) (GDS). This scale has been validated in mild to moderate dementia (25, 26, 27, 28) and was included to allow any effects on mood to be determined.

Controls (60 cases) were a convenience sample recruited from local active retirement groups in the catchment area of the memory clinic who were neither cognitively impaired [defined as MMSE (23) score <24] nor depressed (DSM IV criteria).

The approval of the joint research ethics committee of the Federated Dublin Voluntary Hospitals for this study was granted, and all participants (plus their caregivers in demented groups) signed informed written consent, according to the Helsinki II Declaration, at study outset.

Serum was collected from each subject between 0900 and 1400 h and stored at -20 C until analyzed. Total serum levels of estrone, androstenedione, and testosterone were determined by RIA, and levels of estradiol and cortisol were determined by time-resolved fluoroimmunoassay. Total serum cortisol was included as an index of HPA activity. The endocrine laboratory at Hammersmith Hospital (London, UK) performed the estrone assay. The other assays were performed by the endocrine laboratory at St. James’ Hospital (Dublin, Ireland). Serum estrone was measured using ether extraction followed by RIA with [3H]estrone tracer and charcoal separation. The detection limit was 40 pmol/L, the intraassay coefficient of variation (CV) at low levels was 8.1%, and the interassay CV was 13%. Cross-reactivities at the 50% inhibition level were: with estradiol, 0.18%; with androstenedione, less than 0.01%; with testosterone, less than 0.01%; and with cortisol; less than 0.01%. Recovery rates after spiking serum samples with varying levels of estrone ranged from 92–105%. Serum estradiol was measured using an AutoDELFIA estradiol kit (Wallac Ltd., c/o United Drug PLC, Dublin, Ireland) [detection limit, 40 pmol/L; intraassay CV, 4.4%; interassay CV, 6.9%; cross-reactivity (50% inhibition level) with estrone, 0.75%; cross-reactivity with androstenedione, <0.001%; cross-reactivity with testosterone, <0.01%; cross-reactivity with cortisol, <0.001%; recovery rate, 86–112%]. Serum androstenedione was measured using a Coat-A-Count androstenedione RIA kit (ICN Pharmaceuticals Ireland, Oxon, UK) [detection limit, 0.7 nmol/L; intraassay CV, 5.5%; interassay CV, 8.8%; cross reactivity (50% inhibition level) with estrone, 0.75% cross-reactivity with estradiol, <0.001%; cross-reactivity with testosterone, 0.2%; cross-reactivity with cortisol, 0.02%; recovery rate, 84–115%]. Serum testosterone was measured using a Testo-CT2 RIA kit (Electramed Ltd., Dublin, Ireland) [detection limit, 0.5 nmol/L; intraassay CV, 4.6%; interassay CV, 4.9%%; cross reactivity (50% inhibition level) with estrone, <0.01%; cross-reactivity with estradiol, <0.01%; cross-reactivity with androstenedione, <0.01%; cross-reactivity with cortisol, <0.01%; recovery rate, 90–110%]. Serum cortisol was measured using an AutoDELFIA cortisol kit (Wallac Ltd.) [detection limit, 15 nmol/L; intraassay CV, 3.1%; interassay CV, 1.4%; cross-reactivity (50% inhibition level) with estrone, <0.1%; cross-reactivity with estradiol, <0.1%; cross-reactivity with androstenedione, <0.1%; cross-reactivity with testosterone, 0.3%; recovery rate, 94–107%].

During their visit, subjects (or the main caregiver in the case of demented patients) completed a rater-administered questionnaire that included information about age, years of education, past and current medical history, medication, cigarette-smoking history, and alcohol intake (units of alcohol in past year was estimated by asking how much alcohol consumed on the average per month and multiplied by 12). Medications were recorded if they were taken more than three times a week and were classified according to the British National Formulary (29). Weight (in light clothes without shoes) was measured using an electronic scale accurate to 0.5 kg, and height was measured using a wall-mounted scale accurate to 1 mm. Body mass index (BMI; weight in kilograms divided by height in meters squared) was calculated. Time of assessment was noted.

Undetectable hormone levels occurred in 35.7% (40 of 112) of cases for estradiol (18 of 52 cases and 22 of 60 controls), 1.8% (2 of 112) of cases for androstenedione, and 0.9% (1 of 112) of cases for testosterone. Detectable estrone and cortisol were found in all cases. Undetectable hormone levels were analyzed as occurring at the lower detection limit.

Group differences were analyzed using the Mann-Whitney U test for continuous variables and {chi}2 or Fisher’s exact test for categorical variables. Alcohol intake and time of sample were analyzed by tertile for the multivariate analyses (the lowest tertile was compared with the other two tertiles in each case).

For each of the four sex hormones a linear regression model was constructed. The dependent variable was the serum hormone level, and the independent variable was group membership (AD, n = 1; controls, n = 0). Log transformation of hormone values was used in all regression analyses. The effects of confounding were adjusted for by using as control variables: age, BMI, alcohol intake, time of sample, medication use that differed significantly between the groups (use of a medication was coded as 1, nonuse was coded as 0), cigarette smoking (current smoker = 1, past or never smoked = 0), and serum cortisol level in a series of multivariate regression analyses. Due to the importance of adipose tissue in the production of postmenopausal estrogens a subanalysis was performed using only subjects whose BMI could be matched within 2 kg/m2 of each other. There were 74 subjects (37 in each group) in this analysis. Hormone levels were compared between groups in a manner similar to the main analysis (because of the smaller sample size the number of confounders adjusted for was reduced to age, alcohol intake, and cortisol level).

The assumptions of each model were checked by examining the residuals for normality and constancy of spread. All significance levels reported are two-sided ({alpha} set at 0.05), and all analyses were performed using Datadesk 5.0 software (Data Description, Inc., Ithaca, NY).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline group differences are shown in Table 1Go. There were expected significant differences for age, BMI, and MMSE scores, reflecting that demented subjects were older, had less body mass, and were more cognitively impaired. GDS scores and years of education were also greater in subjects with AD. Alcohol intake was greater in controls. Years since menopause was not calculated for the demented group as there was no way we could validly record it in a cognitively impaired population, but the average age of 77.1 yr suggests that it was 20–30 yr. Duration of dementia was 51.1 (SD, 27.1) months.


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  		Table 1. Group differences

 
A positive family history for dementia (P = 0.0001) was more common among subjects with AD, but there were no differences in medical conditions that might potentially increase dementia risk (such as hypertension, atrial fibrillation, cerebrovascular or cardiovascular disease). Similarly, there was no difference in cigarette-smoking status, with about a fifth of both groups continuing to smoke. There was no difference in the proportion of subjects taking medication (approximately three quarters); however, the use of certain medications [namely cholinesterase inhibitors (9.6% vs. 0%; P = 0.019), antidepressants (17.3% vs. 0%; P = 0.0007), and benzodiazepines (15.4% vs. 3.3%; P = 0.026)] was significantly greater in subjects with AD. No subjects were taking vitamin E or selegeline, and there was no difference in the use of nonsteroidal antiinflammatory drugs (9.6% vs. 10%; P = 0.95).

Differences in hormone levels between groups are shown in Table 2Go. Estrone and androstenedione levels were significantly (P < 0.05) higher in the demented group. After adjusting for age, BMI, cortisol level, alcohol intake, time of sample, cigarette smoking, and use of medications that differed between groups, the differences for estrone and androstenedione remained significant. As a single measure of cortisol is an unreliable measure of HPA axis activity, all analyses were repeated after omitting cortisol as a control variable. Results were unchanged, with estrone (ß = 0.17; SE = 0.061; P = 0.0072) and androstenedione (ß = 0.24; SE = 0.11; P = 0.025) remaining significantly different between groups.


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  		Table 2. Sex hormone values (unadjusted and adjusted)

 
Adjusted levels of cortisol were not calculated, as its presence in this study was as a control variable.

A subanalysis was performed using only subjects whose BMI could be matched within 2 kg/m2 of each other. The results are shown in Table 3Go. Levels of estrone and androstenedione continued to be significantly higher in subjects with AD. Spearman’s nonparametric rank correlation method was used to determine whether MMSE or GDS scores correlated with hormone levels in either group. Apart from a single negative association between the serum cortisol level in the AD group and the GDS score ({rho} = -0.33; P = 0.020), there were no significant correlations.


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  		Table 3. Sex hormone values (unadjusted and adjusted) in a BMI-matched cohort

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study of postmenopausal women the estrogen subtype estrone and its precursor androstenedione were significantly higher in patients with AD compared with controls. This occurred before and after adjusting for confounding factors, including simultaneous cortisol levels, and was present when analysis was restricted to subjects matched for body mass index. Although unexpected, it replicates the findings of Nasman et al. (30), who showed that patients with AD had higher levels of androstenedione than healthy controls. Total serum levels of sex hormones may not correspond to tissue levels of free (i.e. unbound) hormone, which are more likely to be relevant in terms of biological action. Nevertheless, the finding of increased serum levels of sex hormones needs to be explained.

This study has several limitations that need to be considered before the results are discussed. The study was based on a convenience sample. Both cases and controls were community dwelling and were recruited from the same geographical area, and results were adjusted for all factors known to be associated with hormone levels or that differed between groups, but the influence of unknown and unmeasured factors on hormone levels cannot be determined. Hormone levels were based on a single morning sample, which may have obscured the findings with respect to some hormones. This is particularly true for pulsatile hormones such as cortisol. It is worth noting, however, that a 3-yr study looking at the reproducibility of endogenous sex hormones found that intraindividual changes were minimal (10). Serum samples were frozen immediately after sampling and kept for up to 6 months. Although it is possible that changes in hormone values due to storage may have occurred, other researchers have shown that serum levels of steroid hormones are relatively stable when frozen in polypropylene tubes over periods of 3–10 yr (31, 32). Undetectable estradiol occurred in about a third of cases. Although this was akin to the findings of others (33, 34) studying similar postmenopausal populations, it does tend to limit the conclusions that can be drawn for this hormone.

Our results disagree with the recent findings of Manly et al. (35), who found that 50 women with AD had lower serum estradiol levels than 93 control subjects after (and before) adjusting for a variety of potential confounds. However, alcohol intake was not adjusted for in their analyses [there is some evidence that subjects with a regular alcohol intake have significantly higher serum estradiol levels (36)]. It is possible, therefore, that the lower estradiol levels found in their demented subjects reflected a lower alcohol intake among this group. In addition, although subjects using estrogen replacement were excluded, the highest estradiol level noted in their subjects (277 pmol/L) was considerably higher than would be expected in a postmenopausal population (usually <100 pmol/L), suggesting that there may have been some inadvertent use of estrogen replacement by some of the subjects. Lastly, their subject group was ethnically quite diverse, with a majority of subjects being black or Hispanic, whereas all of our subjects were Caucasian. For these reasons, a direct comparison with our results is problematic.

There are several reasons why serum estrogen or its precursors might have been elevated in our subjects with AD. Higher levels of estrogen might be damaging and increase the risk of developing AD. This is biologically implausible given a range of studies showing that estrogen prevents hippocampal degeneration by toxins (37, 38, 39), increases hippocampal synaptic density (40, 41, 42, 43, 44, 45), converts amyloid to a less toxic form (46), and improves verbal memory (47, 48, 49) as well as the aforementioned epidemiological studies showing reduced prevalence of AD in women taking estrogen replacement .Another explanation is that the hormones we are measuring are predominantly subtypes with antagonistic properties. For example, estrone has a C-2 hydroxylated subtype that is a competitive inhibitor of estradiol (50, 51, 52). Although this might explain an elevated estrone level in this context, it fails to explain the elevation in androstenedione found in this study. A third explanation and the one that is probably more likely is that some factor that differed systematically between the groups is responsible. The finding of higher sex hormone levels remained after adjustment for multiple demographic and biological factors. This suggests that variations in these factors between the groups was not responsible for the difference in hormone levels. The possibility that AD itself was responsible for the higher sex hormone levels must therefore be considered, although this will need to be confirmed in subsequent studies.

The finding of higher estrone, but not estradiol, levels may represent a true difference between estrogen subtypes or a lesser ability of a single measurement of serum estradiol to reflect average levels throughout the day (53, 54). It may also reflect the lower sensitivity of the estradiol assay used in this study. Variations in sex hormones were not associated with mood (as assessed by the GDS) or cognition (as assessed by the MMSE) for either group. This replicates the recent findings in two large cohorts of nondemented postmenopausal women that found no association between serum estrogens and mood (34, 55) or cognition (34) and extends them to our group with AD. The significant univariate relationship between serum cortisol and GDS score in subjects with AD is not explained by existing theory and is probably spurious. There were 20 univariate analyses in all, and 1 false positive finding would not be unexpected.

In conclusion, levels of the estrogen subtype estrone and its precursor androstenedione were significantly higher in subjects with AD than in controls after adjusting for a variety of demographic and biological factors (including cortisol). This raises the possibility of an abnormality of sex steroid production in AD that warrants further research.

Received March 4, 2000.

Revised September 5, 2000.

Revised October 31, 2000.

Accepted November 6, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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