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Association Between Physiological Serum Concentration of Estrogen and the Mental Health of Community-Dwelling Postmenopausal Women Age 70 Years and Over

Posted on: Tuesday, 22 February 2005, 03:00 CST

Objective: The authors investigated the association between physiological levels of estrogen and mood/cognitive functioning among older postmenopausal women. Methods: This was a cross- sectional study of 265postmenopausal women (mean age: 74.6years), who were given a semistructuredpsychiatric interview (CAMDEX-R) and self-rated their health with the Beck Depression and Anxiety Inventories (BDI and BAI) and the SF-36 Health Survey. Cognitive abilities were assessed with the cognitive subsection of the CAMDEX (CAMCOG), the Word Lists subtest of the Wechsler Memory Scale, and the Block Design and Verbal Fluency subtests of the Wechsler Adult Intelligence Scale. Estradiol- and estrone-sensitive immunoassays were used to measure serum estradiol and estrone. Results: Women in the lowest 50th percentile of serum estradiol were more likely than women in the highest 50th percentile to have BDI scores suggestive of clinically significant or severe depression. Women in the lowest 50th percentile of serum estrone had higher BAI scores. There was no significant association between serum estradiol/estrone and cognitive functioning. Conclusions: Physiological serum concentrations of estradiol and estrone are inversely associated with depression and anxiety scores in older postmenopausal women. The association between serum estradiol and depression ratings is not linear and seems to be subject to a threshold effect. (Am J Geriatr Psychiatry 2005; 13:142-149)

The world's population is aging rapidly.1 This dramatic demographic change is a desirable and welcome phenomenon, but the social, financial, and health consequences of an aging society cannot be ignored. Old age is associated with increased vulnerability and susceptibility to disease and disability. Movement disorders, osteoporosis, arthritis, cancer, sensory deficits, cardiovascular diseases, depression, and dementia are all highly prevalent in later life. Dementia and depression, for example, are the most frequent mental health disorders of older people and the two leading causes of years of life lost to disability in many parts of the world.2 It is clear, therefore, that the identification of potentially modifiable factors associated with dementia and depression in later life is a major public health priority.

Sex hormones, or lack of them, have been previously associated with both dementia and depression. A recent systematic review and meta-analysis of case-control and cohort studies found that hormone replacement therapy (HRT) is associated with decreased risk of dementia (odds ratio [OR]: 0.7; 95% confidence interval [CI]: 0.6- 0.9), although all observational studies available had significant methodological limitations.3 The results of in vitro and animal studies published to date have lent further support to the notion that estrogen is neuroprotective and improves cognitive functioning,4 but recently published findings from the Women's Health Initiative trial have contradicted this prediction.5 A total of 2,229 women were randomized to treatment with 0.625 mg of conjugated equine estrogen+ 2.5 mg of medroxyprogesterone acetate, versus placebo (N = 2,303). After a mean follow-up period of 4 years, 40 women in the active and 21 in the placebo group received the diagnosis of dementia (hazard ratio [HR]: 2.0; 95% CI: 1.2- 3.5).

The potential effects of estrogen on mood are also debatable. The results of animal studies show that estrogen modulates serotonin and noradrenergic function in the brain. Most of the available evidence indicates that estrogen increases postsynaptic responsivity, number of receptors, and serotonin uptake and synthesis. Also, estrogen upregulates 5-HT^sub 1^ and downregulates 5-HT^sub 2^ receptors, increases the turnover of noradrenaline, decreases noradrenaline uptake from the synaptic cleft, inhibits monoamine oxidase activity, and enhances β-adrenoceptor binding.6 Taken together, such findings suggest that estrogen has pharmacodynamic properties that are, to some degree, similar to those of typical antidepressant medications. Preliminary evidence from clinical studies further supports a mood-regulating role for estrogen.7 For example, two small randomized trials of estrogen-replacement therapy for the treatment of depression in perimenopausal and postmenopausal women reported that women receiving active treatment experienced significantly greater decline in depression scores and were more likely to experience full remission of symptoms than women treated with placebo patches.8,9

Overall, most studies available to-date have limited the investigation of the association between estrogen and cognitive functioning/mood to relatively young perimenopausal or postmenopausal women, so that it remains unclear whether the purported mental health effects of estrogen are relevant for older postmenopausal women. We designed the present study with the aim of clarifying whether physiological estradiol and estrone levels are associated with cognitive functioning and mood in women age 70 years and over.

METHODS

This cross-sectional study recruited women age 70 years and over, living independently in the metropolitan area of Perth, Western Australia. They were volunteers recruited through advertisements in the local press for an ongoing project designed to investigate mood and well-being among older women. Subjects were excluded from participating in the study if they: 1) had Mini-Mental State Exam total score (MMSE) lower than 24 points; 2) were not fluent in English; 3) had severe sensory impairment; 4) had a previous clinical history of stroke or current or previous hazardous drinking; and 5) used hormone replacement therapy during the 6 months before assessment.

Clinical Assessment

All participants were interviewed with the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX-R),10 a reliable semistructured interview designed to assess mental state and cognitive functioning of older adults.

Depressive symptoms were assessed with the Beck Depression Inventory (BDI)," which is a self-rating scale designed to evaluate the severity of depression in clinical and research settings. It includes 21 questions with possible ratings ranging from O to 3. The BDI has high internal consistency (≥0.86) and is sensitive to change in the severity of depression.11 The scale does not allow for an established diagnosis of a major depressive episode, but scores of 13 or more have been shown to be associated with clinically significant depressive symptoms.11

The Beck Anxiety Inventory (BAI) was used for the assessment of anxiety symptoms.12 This self-rating scale includes 21 items describing common symptoms of anxiety that can be rated according to their intensity from O to 3. Internal consistency (K = 0.92) and test-retest reliability ratings (r-0.75) are high, and so are different measures of validity.12 Scores of 13 or more indicate the presence of clinically significant anxiety symptoms.12

The SF-36 was used to assess quality of life.13 This questionnaire consists of 36 items designed to assess eight different health-related areas (physical functioning, physical role, body pain, general health, vitality, social functioning, emotional role, and mental health) as well as physical and mental health summary measures. Published internal-consistency and test-retest reliability statistics are in excess of 0.70, and validity is also considered to be appropriate.13

Body Mass Index

Weight was measured to the nearest kg. Height was measured to the nearest 0.5 cm, using a wall-mounted stadiometer. Body Mass Index (BMI) was calculated as weight in kg divided by height in cm- squared (kg/ cm^sup 2^).

Cognitive Assessment

The neuropsychological assessment of participants included the investigation of specific and general measures of functioning. The Cambridge Cognitive Examination for Mental Disorders of the Elderly (CAMCOG)10 is divided into several subsections measuring various aspects of cognitive functioning: orientation, language, memory, attention and concentration, praxis, perception, calculation, and executive functions. The total score can range from 0 to 105 (higher scores indicating better cognitive performance), and is highly correlated with the MMSE total score (which can also be computed from the CAMCOG).10 Reported test-retest reliability scores are greater than O.S.10

Word Lists (WL)14 measures immediate and delayed memory for verbal material. Subjects are presented with a list of 12 semantically unrelated words and then asked to recall as many words as possible. This procedure is repeated for three additional trials, for a total of four learning trials. Then the examiner reads a new word list and asks the subject to recall the words on this list and, subsequently, on the first list. In WL II, the examinee is asked to recall the first list or words (delayed recall). Then the examiner reads a list of 24 words and asks the examinee to identify each word as either one he or she was asked to remember or a new word (recognition). For the purposes of this study, we computed and analyzed the Recall Total Score (sum of Trials 1 to 4), Recognition Total Score, and Percent Retention (delayed recall/ word list recall for Trial 4) X 100)\.

Block Design (BD)15 is a constructional test in which the subject is presented with four or nine colored blocks. The aim is to use the blocks to construct replicas of 10 designs printed in a booklet. This is a sensitive test of visuospatial organization, with the total possible score ranging from O to 68 points.

Finally, verbal fluency (VF) was investigated by asking subjects to name as many words as possible starting with the letters /, a, and s, as well as animals (1 minute each). The VF total score represents the sum of the number of words produced for each one of the four trials.

Biochemical Analysis

Blood from fasting subjects was collected for serum and into EDTA for plasma with separation within 1 hour (all samples were collected between 8:00 A.M. and 9:00 A.M.). The SPECTRIA estradiol-sensitive immunoassay test was used to ascertain the serum concentration of unconjugated 17β-estradiol (Spectria Oestradiol[125I]- Sensitive Coated Tube Radiommunoassay, Orion Diagnostica; 2001). The coefficient of variance (CV) for this assay is 5%. Cross-reactivity of this assay for other estradiol-related steroids (including estrone) has been established and is, on the whole, well below 1%. Similarly, serum estrone was determined with InterTech Oestrone Direct Radioimmunoassay CT (InterTech; 2000), which has a CV of approximately 5% and low cross-reactivity with other steroids, including estradiol (1.2%).

Statistical Analysis

Data were analyzed with the statistical package Stata, Release 8.2.16 Descriptive statistics were used to determine frequencies, means, standard deviation (SD), and distribution of data. We investigated the frequency distribution on contingency tables by use of Pearson's chi-square method. Student's f-test was used for between-group comparisons of normally distributed data, and the Mann- Whitney test was used to analyze ranked data, such as BDI scores. The Spearman correlation coefficient (p) was used to investigate the association between ordinal variables. Analysis of covariance (ANCOVA) was used to investigate the association between estradiol/ estrone group membership and BDI and BAI scores, taking into account the effects of BMI. Alpha value was set at 0.05, and all tests were two-tailed.

TABLE 1. Demographic and Clinical Characteristics of Women Grouped by 50th Percentile of Serum Estradiol

TABLE 2. Demographic and Clinical Characteristics of Women Grouped by 50th Percentile of Serum Estrone

The study was approved by the Ethics Committee of the University of Western Australia. Subjects gave written informed consent for the collection, storage, and analysis of blood samples and DNA.

RESULTS

A total of 265 women volunteered and met the study's inclusion/ exclusion criteria. Their mean age was 74.6 (SD: 4.2) years; 40.4% were married, and 53.6% had more than the required minimum statutory education. Their serum estradiol ranged from 9 pmol/L to 161 pmol/L (mean: 27.4; SD: 16.8), with a median of 24 pmol/L (information on estradiol level was not available for 5 of the 265 participants). Because of marked skewness in the distribution of estradiol levels, subjects were divided into two groups according to median estradiol level. Table 1 summarizes the demographic and clinical characteristics of women below and above the 50th percentile of serum estradiol. Women above the 50th percentile had significantly higher BMI and lower BDI total scores than women below the 50th percentile. Women in the higher 50th percentile of serum estradiol were also significantly less likely to present with clinically significant depressive symptoms (BDI ≥10) or severe depression (BDI ≥17; 11/127 versus 4/133; χ^sup 2^^sub [1]^ = 3.82; p = 0.051). A post-hoc analysis of the data dividing participants into quartiles showed that subjects in the lowest and second-lowest estradiol quartile do not differ in terms of their BDI scores (mean: 6.3, SD: 4.5, and mean: 6.8, SD: 4.7, respectively; p = 0.596). Likewise, women in the two highest estradiol quartiles had similar BDI scores (mean: 8.1, SD: 6.1, and mean: 8.0, SD: 5.1, respectively; p = 0.866).

FIGURE 1. Scatterplot Distribution of Beck Depression Inventory (BDI) Scores by Serum Estradiol Levels

A similar approach was used to investigate the association between serum levels of estrone and abnormalities in mood and cognitive functioning (median serum estrone: 29 pmol/L; Table 2). Women in the higher 50th percentile of serum estrone had significantly less intense anxiety symptoms and were less likely to present with clinically significant anxiety. The association between estrone-group membership and BAI scores was found to be independent from BMI (ANCOVA: F^sub [1,198]^ = 9.07; p = 0.003).

There was no significant association between cognitive functioning, as measured by the CAMCOG, and serum estradiol or estrone (Table 1, Table 2).

There was a significant direct correlation between BDI and BAI scores (N = 265; Spearman p = 0.51; p <0.001), as well as between estradiol and estrone levels (N = 255; Spearman p = 0.43; p <0.001).

DISCUSSION

The results of the present study showed that physiological concentrations of serum estradiol and estrone are associated with mood and quality of life, but not with cognitive functioning, in older, postmenopausal women. Interestingly, our findings suggest that the association between estradiol levels and depression scores is not linear (Figure 1). Instead, there seems to be a threshold effect after which the mood-regulating effect of estrogen becomes apparent. An alternative explanation for such a finding is that the sensitivity of the assay diminishes with decreasing serum estradiol, so that its discriminatory power at the lower end of the spectrum is compromised (i.e., a substantial proportion of the variance below estradiol levels of 24 pmol/L could be due to assay error [the known CV of the assay for estradiol levels below 17 pmol/L is 18%]). Although we are unable to dismiss such a possibility altogether, it would seem that a threshold-effect explanation is more consistent with our findings, particularly because there was no difference between women in the two highest quartiles of estradiol levels in relation to their BDI scores.

Serum estrone concentrations were inversely associated with anxiety symptoms, which, in turn, were positively correlated with depression scores. There is ample evidence from clinical studies and epidemiological surveys that depression and anxiety are closely related, particularly in later life.17 It is unclear how estrone could preferentially mediate the expression of anxiety symptoms among older, postmenopausal women, but one possibility is that some of the somatic symptoms assessed by the BAI, such as facial flushing or feeling hot, may also be associated with low serum estrone. We reanalyzed our BAI data, removing the nine somatic items of the scale, and subjects in the lower 50th percentile still showed higher BAI scores than women in the higher 50th percentile of serum estrone (p = 0.048). Hence, the observed association cannot be simply explained by confounding.

Previous reports have highlighted the potential relationship between estrogen and mood in cases of premenstrual dysphoria,18,19 postnatal depression,20,21 and depression in the perimenopause.22 There is also preliminary evidence from a small randomized, placebo- controlled trial suggesting that estradiol has clinically significant antidepressant properties. Scares et al.9 randomized 50 depressed women to treatment with 100 g of estrogen or placebo patches. They found that 16 of 25 women on ERT had full remission of symptoms after 12 weeks of treatment, versus only 7 of 25 treated with placebo (OR: 4.6; CI: 1.4-14.8).

The association between estrogen and mood during the postmenopausal period has not as yet been adequately explored, although currently available evidence seems to be consistent with a mood-regulating role for the hormone. For example, Schneider et al.23 retrospectively reviewed the antidepressant effect of hormone replacement therapy on treatment response to fluoxetine and observed a significant interaction between hormonal status and treatment effect. More recently, Schneider et al.24 used the same approach to evaluate the interaction between hormone replacement therapy and treatment response to sertraline in depressed postmenopausal women recruited into two multicenter trials. The results showed that women receiving estrogen had better quality of life and Clinical Global Impression ratings at the end of the study than women receiving sertraline but not hormone replacement therapy.

More recently, two large, randomized, placebocontrolled trials of estrogen-plus-progestin (Heart and Estrogen/Progestin Replacement Trial [HERS] and the Women Heath Initiative Trial [WHI]) have investigated the association between hormone replacement and mood. The HERS reported data on 2,246 older women (mean age: 66.4) who were followed up for 36 months. Women receiving active treatment had significantly fewer depressive symptoms at the end of the follow-up period than women treated with placebo, particularly if they were also experiencing "flushes."25 However, the WHI, which recruited 16,608 women, age 50 to 79 years, failed to find a significant effect of estrogen-plus-progestin on depression scores over a follow- up period of 3 years.26

It is also possible that the association between estrogen and mood in our sample is at least partly explained by other unmeasured factors, such as vasomotor symptoms, progesterone levels, diet, physical activity, and social engagement. It is possible, for example, that women who are fitter have better mood and also higher serum concentration of estrogen. The design of our study did not enable us to adequately explore this possibility, but the results of previously discussed randomized clinical trials on estrogen replacement therapy for the treatment of depress\ion are consistent with the hypothesis that estrogen has mood-regulating properties.

Our finding that estradiol and estrone have different associations with depression and anxiety scores was unexpected. The results of experiments with ovariectomized rats suggest that estradiol-but not estrone-replacement, decreases GABA content.36 This may partly mitigate the "anti-anxiety" effect of estradiol but not of estrone. At this point in time, such an explanation of our results is nothing but speculative, but it serves to highlight the slightly dissimilar actions that different types of sex hormones may have in the brain.

Finally, our study was unable to demonstrate an association between estrogen levels and cognitive performance. Previous reports had suggested that estradiol concentration may be directly associated with cognitive abilities27 and may predict the risk of cognitive decline at follow-up.28 However, findings from The Rotterdam Study indicate that serum estradiol is not associated with memory performance or hippocampal volume,29 nor with the subsequent risk of dementia.30 Also, the results of the HERS31 and WHI trials32 showed that HRT not only fails to improve cognitive performance, but increases the risk of cognitive decline32 and dementia.5 Taken together, these results would suggest that estrogen is unlikely to play a clinically meaningful role in the modulation of cognitive functioning among older, postmenopausal women.

In summary, the results of our cross- sectional survey indicate that the physiological concentrations of estradiol and estrone observed among older, postmenopausal women are significantly associated with mood and well-being. However, it seems unlikely that standard HRT will ever become a practical treatment option for depression in later life, because its use is associated with unacceptable heath risks.33 Nonetheless, the potential beneficial effect of relatively small doses of estrogen on mood warrants further investigation.34 Also, a better understanding of : estrogen- mediated antidepressant mechanisms may lead to the development of new and potentially useful forms of treatment for mood disorders in later life. For example, selective estrogen-receptor (SER) modulators, such as raloxifene, have been developed to improve tissue specificity and decrease unwanted side effects.35 Currently available SER modulators do not cross the blood-brain barrier particularly well, but, as a group, they show that there is potential for new agents with greater affinity for brain tissue to be developed in the near future.

This project was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC). We thank Kettle Cassidy, Ria Kotynia, and Tricia Knox for their assistance with data collection and management. Finally, the investigators gratefully acknowledge the generous contribution of the women who took part in this study.

References

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Osvaldo P. Almeida, M.D., Ph.D., FRANZCP, Nicola Lautenschlager, M.D., Ph.D. Samuel Vasikaram, MBBS, M.D., FRCPA, Peter Leedman, MBBS, Ph.D., FRACP Leon Flicker, MBBS, Ph.D., FRACP

Received January 4, 2004; revised February 16, March 25, 2004; accepted March 26, 2004. From the School of Psychiatry and Clinical Neurosciences, University of Western Australia, and the Dept. of Psychiatry, Royal Perth Hospital (OPA1NL), the School of Surgery and Pathology, University of Western Australia, and the Dept. of Biochemistry, Royal Perth Hospital (SV), the School of Medicine and Pharmacology, University of Western Australia (PL1LF), the Dept. of Endocrinology and Diabetes, Royal Perth Hospital (PL), the Laboratory for Cancer Medicine, Centre for Medical Research, the Western Australian Institute for Medical Research (PL), and the Dept. of Geriatric Medicine, Royal Perth Hospital (LF). Send correspondence and reprint requests to Prof. Osvaldo P. Almeida, UWA School of Psychiatry and Clinical Neurosciences (M573, Level 6, Ainslie House, Royal Perth Hospital, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia, e-mail: osvalm@cyllene.uwa.edu.au

2005 Amer\ican Association for Geriatric Psychiatry

Copyright American Psychiatric Press, Inc. Feb 2005

Source: American Journal of Geriatric Psychiatry, The

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