- Email: [email protected]
HRT and cognitive function
International Congress Series 1229 (2002) 45 – 52
HRT and cognitive function Risto Erkkola*, Pa¨ivi Polo-Kantola Department of Obstetrics and Gynaecology, University Central Hospital, FIN-20520 Turku, Finland
Abstract In the last two decades, the cognitive functioning of ageing females and the effect of hormone replacement therapy (HRT) has been the subject of many studies. The results have been contradictory; while in some studies a beneficial effect has been found, other studies have shown no effect. This discrepancy may be due to different populations, methods and administrations of HRT. It seems reasonable to state that many postmenopausal women may retain a high cognitive ability without any additional benefit from HRT, while some postmenopausal women may gain benefit from the therapy. It remains to further investigations to define and detect those subjects who might gain significant advantage from the treatment. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Cognitive functioning; Hormone replacement therapy; Menopause
1. Introduction Research on female climacteric has made great progress during the last two decades. Recently, more attention has been paid on the relations between sex steroid levels and mood, psyche and cognitive function [1]. Climacteric women experience several mental symptoms, the most frequently reported of which are anxiety, depression, the decline of libido, the lack of concentration, and memory impairment [2– 4]. The purpose of this review is to elucidate the current view on the effect of menopause and hormone replacement therapy (HRT) on cognitive functions of postmenopausal females.
2. The effect of estrogen on the brain The molecular and metabolic effects of estrogen on brain function have been the subject of many review articles [5]. We refer to them, and present briefly the central view on the *
Corresponding author. Tel.: +358-2-2612-300; fax: +358-2-2612-340. E-mail address: [email protected] (R. Erkkola).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 4 7 5 - 7
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R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
Table 1 Literature review of studies on hormone replacement therapy in female postmenopause and cognitive functioning Refs. [7 – 25] Study
Study design
Subjects
Findings
Comment
[7]
unblinded, non-placebocontrolled nonrandomized trial, 6 months
no improvement in the four cognitive tests or mood measures
[8]
unblinded, non-placebocontrolled nonrandomized trial, 6 months
56 surgically menopausal (29 on ERT) and 32 hysterectomized women, aged 46 years 27 climacteric, aged 46 years, 26 postmenopausal women, aged 55 years, on ERT and progestin (1 month)
[9]
double-blind, placebocontrolled, randomized trial, 3 months
26 surgically or naturally menopausal women, aged 58 years; 11 on estriol, 15 on placebo
menopausal symptoms or education not adjusted for between the groups duration only 1 month, and effect of progestin, age and education not controlled; testing after five ‘‘wash-out’’ months may show learning effect effects of mood, menopausal symptoms or education controlled
[10]
double-blind, placebocontrolled, randomized trial, 6 months
18 surgically or naturally menopausal women, aged 29 – 68 years: nine on estrogen, nine on placebo
[11]
double-blind, placebocontrolled, randomized, cross-over trial, 4 months double-blind, randomized, cross-over trial, 3 months
64 peri- or postmenopausal women on estrogen and placebo
improvement on a self-rating memory scale during ERT vs. placebo
50 surgically menopausal women, aged 45 years, divided to five groups (three groups on HRT, one on placebo and one control)
improvement in all four tests used (Digit Span, verbal and visuomotor tests) during HRT vs. placebo
[12]
improvement in one of six cognitive tests after 1 month, and in all tests and mood scales after 6 months improvement on one alertness performance of nine cognitive tests in ERT group improvement in five of the six Guild memory subtests, compared with baseline in the estrogen group
estrogen and placebo groups were not compared; effects of age, mood, menopausal symptoms or education not controlled only self-rating was used; age and education not reported; menopausal symptoms not adjusted for the analyses were not adjusted for education, age, mood or menopausal symptoms
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
47
Table 1 (continued ) Study
Study design
Subjects
Findings
Comment
[13]
double-blind, placebocontrolled, randomized trial, 3 months
[14]
double-blind, placebocontrolled, randomized trial, 2 months prospective cohort, cognitive testing after 15 years of enrollment cross-sectional
36 surgically menopausal women, aged 53 years, two groups on estrogen and one on placebo 19 surgically menopausal women, aged 48 years; 10 on estrogen and nine on placebo 800 women: current (34% on ERT) past and non-estrogen users, aged 65 – 95 years 71 postmenopausal women, aged 55 and older, 39% on ERT with/without progestin
no improvement in the cognitive tests (Digit Span, Digit Symbol); depression improved improvement in one of four cognitive tests (paragraph recall) during estrogen no differences between the groups in MMSE, verbal or visual memory tests estrogen-users performed better in two of six verbal tests (paragraph recall measures) estrogen-users performed better on one of the two verbal memory tests administered estrogen-users ‘‘had better scores’’ on several verbal and nonverbal tests administered
the subjects were vasomotorically asymptomatic; the groups were not matched for education, and not compared the two groups were not matched for menopausal symptoms or education, and were not statistically compared the study was a part of a heart disease survey; age and education but not depression were adjusted for estrogen-users and nonusers were matched for age, but not for education or depression; progestin use not controlled; only verbal tests used estrogen-users and nonusers were matched for age and education, but not for progestin use and depression results or statistical comparisons not reported; the study groups were matched for age but not for education or depression ERT was evaluated 5 years before testing, only one test was used; age but not education or depression were adjusted for education but not depression was adjusted for analyses; only one cognitive test was administered
[15]
[16]
[17]
cross-sectional, case-control
72 postmenopausal women on ERT/HRT, and 72 nonusers, aged 55 – 93 years
[18]
cross-sectional
54 postmenopausal women, 39% on ERT with/without progestin, aged 50 and older
[19]
cross-sectional, case-control
214 women, mean age 80 years (21% on ERT)
no differences between the groups in Clock Drawing test
[20]
cross-sectional
288 postmenopausal women (40% on ERT), age of users 62 and nonusers 68 years
estrogen-users performed better on visual memory (BVR)
(continued on next page)
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R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
Table 1 (continued ) Study
Study design
Subjects
[21]
cross-sectional
15 ERT-users with/ without progestin, aged 65 years; 17 nonusers, aged 68 years
[22]
prospective cohort, community-based epidemiological study
727 women, mean age 74 years; 11% had used ERT
[23]
cross-sectional
14 ERT-users with/ without progestin; 41 non-users; age 65 and older
[24]
prospective cohort
9651 women, aged 65 and older; current, past and non-use of ERT was documented
[25]
A trial of estrogen effects using functional MRI
46 postmenopausal women, aged 33 – 61 years
Findings estrogen-users performed better on two memory tests (verbal and visual), but not on other 10 tests estrogen-users performed better in all four verbal tests
estrogen-users performed better on Digit-Span, but similarly to nonusers in other 12 cognitive measures current ERT users did not perform better on MMSE and the two visuomotor tests estrogen increased brain activation patterns differently during phases of working memory
Comment ERT use was not unopposed; the groups were matched on age and education, but not on depression
effect of age and education was controlled, but not effects of depression; the mean time since ERT was 25 years ERT-use was not unopposed; only one difference favored estrogen users in a comprehensive test battery effect of age, education and activity limitations were adjusted for; only three tests were administered the group was rather heterogeneous in relation to age and cause of menopause; estrogen had effects on working memory
mechanisms by which estrogen exerts its action on the brain and neurons. Estrogen receptors exist in several brain areas, including the cortex, hippocampus, amygdala, thalamus, hypothalamus, the basal forebrain and the preoptic area. These areas are involved in several cognitive functions; in particular, attention and memory. Although the precise action of estrogen in the brain is not clear, several mechanisms have been suggested. Estrogen induces the synthesis and activation of choline acetyltransferase, the rate-limiting enzyme in acetylcholine formation, as well as potassium-stimulated acetylcholine release in certain brain areas. By inducing the degradation of monoamine oxidase, estrogen enhances the activity of noradrenaline and dopamine in neural pathways involved in cognitive functions. Furthermore, estrogen regulates serotonin transport and binding in the brain. Estrogen upregulates dopamine receptors and interferes with catechol-Omethyltransferases, the enzyme catabolizing dopamine and noradrenaline. Although the exact nature of the estrogen effect on GABA is not completely clear, changes in both the release and re-uptake of GABA appear to be involved. Estrogen also has direct effects on neurons by stimulating axonal sprouting and dendritic spine formation. In hippocampal neurons, it increases dendritic spine density by reducing GABA neurotransmission. Evidence is also available to suggest that estrogen
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
49
could prevent neuronal atrophy. Estrogen may protect against cerebral ischemia by inducing central nervous system vasodilatation, slowing cerebral atherosclerosis and thus possibly preventing vascular dementia and other cognitive decline. Hence, there is a wealth of evidence making it biologically plausible to suggest the benefit of estrogen for brain function.
3. Effect of endogenous estrogen on cognition in postmenopausal women without HRT Yaffe et al. [6] studied the relationship between non-protein-bound or bioavailable estradiol and cognitive performance assessed with a modified Mini Mental Status Examination of women aged 65 or older. The testing was carried out at the baseline and after 6 years. The non-protein-bound and bioavailable estradiol were determined from the baseline-stored serum. Cognitive impairment occurs about three-fold more often in the lowest tertile in comparison with the highest tertile. In an earlier study, they did not find any benefit from the high total estradiol level.
4. Effects of HRT on cognition Previous studies on the effect of HRT/ERT on cognitive functions in samples of nondemented women have yielded conflicting results (Table 1, Refs. [7 –25]). The study methods were subjective questionnaires, semi-objective psychological tests and new methods with computer technology and based on the reaction time and the rate of mistakes made. Further, the lack of consistency between these studies has been attributed to other factors such as: small numbers of subjects recruited, differences in the estrogen preparations and their doses, the difference in the ages or the symptomatology of the subjects in the study populations, as well as the differences in the type of menopause (natural or surgical). Furthermore, there has frequently been a failure to distinguish between the effects of hormones on mood and depressive symptoms from an independent effect on cognition.
5. Own studies In our battery of studies, the following projects were carried out: (1) we investigated the effect of the severity of climacteric symptoms on cognitive functioning. Despite subjective complaints of memory impairment in association with climacteric vasomotor symptoms, our results did not support a direct cause- and effect relationship [26]. (2) In the second project, we designed a prospective, randomized, placebo-controlled, crossover study, whereby 70 healthy postmenopausal women were included. Three months’ estrogen replacement therapy (ERT) had no effect on cognitive functions. In that population, estrogen was not superior to placebo in any task of our comprehensive test battery. In those
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healthy and relatively young postmenopausal women, cognitive performance was well preserved. Observed cognitive changes were mild and primarily age-related, and not reversible by ERT ([26], Table 2). (3) In the third project, we compared two groups, one with an estrogen level of 25 –50 pmol/l (mean 43 pmol/l) and another with a higher estrogen level of 105 – 424 pmol/l (mean 249 pmol/l). Estrogen levels did not affect the cognitive performance ([28], Table 2). Table 2 Summary of own studies. The first study was a prospective, randomized, double-blinded, placebo-controlled cross-over study to investigate the effect of estrogen replacement therapy on the cognitive functions in postmenopausal women [27]. In the second study, subjects with a high estrogen level, either endogenous or exogenous, were compared with the subjects with low estrogen level [28] Test
Effect of ERT on cognition
Effect of estrogen concentration, (high vs. low)
Automatic processing Letters (six different targets) Numbers (four different targets) All targets
NS NS NS
NS NS NS
Reaction time tests SRT 2-CRT 10-CRT Subtraction test Verification test
NS NS NS NS NS
NS NS NS NS NS
Tests for controlled processing and working memory Subtraction time NS Verification time NS
NS NS
Attention Vigilance, reaction time Vigilance, errors Stroop
NS NS NS
NS high estrogen better NS
ND NS NS ND NS ND ND ND ND ND
NS NS NS NS NS NS NS NS NS NS
NS NS
NS NS
Verbal and nonverbal performances Similarities Digit Span Digit symbol Block design Benton visual retention test 20 objects naming time 20 objects immediate recall 20 objects delayed recall 30 PWA immediate recall 30 PWA delayed recall Auditorial verbal memory PASAT easy form PASAT difficult form
SRT = simple reaction time, CRT = choice reaction time, PWA = paired word associates, PASAT = paced auditory serial addition test, NS = nonsignificant, ND = not done.
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6. Conclusion Our studies of healthy postmenopausal women of 45 –65 years of age and computerbased cognition study methodology showed that the cognitive functioning was independent of severity of climacteric symptoms, estrogen therapy or estrogen level. Future studies on cognition in postmenopausal females should probably focus on older age groups, longer duration of treatment and patients with cognitive deterioration.
Acknowledgements Our studies received financial support from the Academy of Finland.
References [1] R. Erkkola, Female menopause, hormone replacement therapy, and cognitive processes, Maturitas 23 (1996) S27 – S30. [2] M. Hunter, R. Battersby, M. Whitehead, Relationships between psychological symptoms, somatic complaints and menopausal status, Maturitas 8 (1986) 217 – 228. [3] R. Erkkola, P. Holma, T. Ja¨rvi, S. Nummi, R. Punnonen, T. Raudaskoski, K. Rehn, M. Ryyna¨nen, P. Sipila¨, E. Tunkelo, A. Virkkunen, T. Virtavuo, O. Ylikorkala, Transdermal oestrogen replacement therapy in a Finnish population, Maturitas 13 (1991) 275 – 281. [4] A. Oldenhave, L.J. Jaszmann, A.A. Haspels, W.T. Everaerd, Impact of climacteric on well-being, A survey based on 5213 women 39 to 60 years old, Am. J. Obstet. Gynecol. 168 (1993) 772 – 780. [5] S.J. Birge, The role of ovarian hormones in cognition and dementia, Neurology 48 (Suppl. 7) (1997) S1 – S41. [6] K. Yaffe, L.-Y. Lui, D. Grady, J. Cauley, J. Kramer, S.R. Cummings, Cognitive decline in women in relation to non-protein-bound oestradiol concentrations, Lancet 356 (2000) 708 – 712. [7] L. Rauramo, K. Lagerspetz, P. Engblom, R. Punnonen, The effect of castration and peroral estrogen therapy on some psychological functions, Front. Horm. Res. 8 (1975) 133 – 151. [8] P. Fedor-Freybergh, The influence of estrogen on the wellbeing and mental performance in climacteric and postmenopausal women, Acta Obstet. Gynecol. Scand. (Suppl. 64) (1977) 1 – 91. [9] G. Vanhulle, R. Demol, A double-blind study into the influence of estriol on a number of psychological test in postmenopausal women, in: P.A. van Keep, R.B. Greenblatt, M. Albeaux-Fernet (Eds.), Consensus on Menopausal Research, MTP Press, London, 1976, pp. 94 – 99. [10] B.W. Hackman, D. Galbraith, Replacement therapy with piperazine oestrone sulfate (Harmogen) and its effects on memory, Curr. Med. Res. Opin. 4 (1976) 303 – 306. [11] S. Campbell, M. Whitehead, Oestrogen therapy and the menopausal syndrome, Clin. Obstet. Gynecol. 4 (1977) 31 – 47. [12] B.B. Sherwin, Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women, Psychoneuroendocrinology 13 (1988) 345 – 357. [13] E.C. Ditkoff, W.G. Crary, M. Cristo, R.A. Lobo, Estrogen improves psychological function in asymptomatic postmenopausal women, Obstet. Gynecol. 78 (1991) 991 – 995. [14] S.M. Phillips, B.B. Sherwin, Effects of estrogen on memory function in surgically menopausal women, Psychoneuroendocrinology 17 (1992) 485 – 495. [15] E. Barrett-Connor, D. Kritz-Silverstein, Estrogen replacement therapy and cognitive function in older women, JAMA 269 (1993) 2637 – 2641. [16] D.L. Kampen, B.B. Sherwin, Estrogen use and verbal memory in healthy postmenopausal women, Obstet. Gynecol. 83 (1994) 979 – 983. [17] D. Robinson, L. Friedman, R. Marcus, J. Tinklenberg, J. Yesavage, Estrogen replacement therapy and memory in older women, J. Am. Geriatr. Soc. 42 (1994) 919 – 922.
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[18] D. Kimura, Estrogen replacement therapy may protect against intellectual decline in postmenopausal women, Horm. Behav. 29 (1995) 312 – 321. [19] A. Paganini-Hill, V.W. Henderson, The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women, J. Am. Geriatr. Soc. 44 (1996) 818 – 822. [20] S.M. Resnick, J. Metter, A.B. Zonderman, Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology 49 (1997) 1491 – 1497. [21] S.M. Resnick, P.M. Maki, S. Golski, M.A. Kraut, A.B. Zonderman, Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance, Horm. Behavior 34 (1998) 171 – 182. [22] D.M. Jacobs, M.-X. Tang, Y. Stern, M. Sano, K. Marder, K.L. Bell, P. Schofield, G. Dooneief, B. Gurland, R. Mayeux, Cognitive function in nondemented older women who took estrogen after menopause, Neurology 50 (1998) 368 – 373. [23] L.E. Carlson, B.B. Sherwin, Steroid hormones, memory and mood in a healthy elderly population, Psychoneuroendocrinology 23 (1998) 583 – 603. [24] K. Matthews, J. Cauley, K. Yaffe, J.M. Zmuda, Estrogen replacement therapy and cognitive decline in older community woman, J. Am. Geriatr. Soc. 47 (1999) 518 – 523. [25] S.E. Shaywitz, B.A. Shaywitz, K.R. Pugh, R.K. Fulbright, P. Skudlarski, W.E. Mencl, R.T. Constable, F. Naftolin, S.F. Palter, K.E. Marchione, L. Katz, D.P. Shankweiler, J.M. Fletcher, C. Lacadie, M. Keltz, J.C. Gore, Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks, JAMA 281 (1999) 1197 – 1202. [26] P. Polo-Kantola, R. Portin, T. Koskinen, O. Polo, K. Irjala, R. Erkkola, Climacteric symptoms do not impair cognitive performances in postmenopause, Maturitas 27 (1977) 13 – 23. [27] P. Polo-Kantola, R. Portin, O. Polo, H. Helenius, K. Irjala, R. Erkkola, The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women, Obstet. Gynecol. 91 (1998) 459 – 466. [28] R. Portin, P. Polo-Kantola, O. Polo, T. Koskinen, A. Revonsuo, K. Irjala, R. Erkkola, Serum estrogen level, attention, memory and other cognitive functions in middle-aged women, Climacteric 2 (1999) 115 – 123.
HRT and cognitive function Risto Erkkola*, Pa¨ivi Polo-Kantola Department of Obstetrics and Gynaecology, University Central Hospital, FIN-20520 Turku, Finland
Abstract In the last two decades, the cognitive functioning of ageing females and the effect of hormone replacement therapy (HRT) has been the subject of many studies. The results have been contradictory; while in some studies a beneficial effect has been found, other studies have shown no effect. This discrepancy may be due to different populations, methods and administrations of HRT. It seems reasonable to state that many postmenopausal women may retain a high cognitive ability without any additional benefit from HRT, while some postmenopausal women may gain benefit from the therapy. It remains to further investigations to define and detect those subjects who might gain significant advantage from the treatment. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Cognitive functioning; Hormone replacement therapy; Menopause
1. Introduction Research on female climacteric has made great progress during the last two decades. Recently, more attention has been paid on the relations between sex steroid levels and mood, psyche and cognitive function [1]. Climacteric women experience several mental symptoms, the most frequently reported of which are anxiety, depression, the decline of libido, the lack of concentration, and memory impairment [2– 4]. The purpose of this review is to elucidate the current view on the effect of menopause and hormone replacement therapy (HRT) on cognitive functions of postmenopausal females.
2. The effect of estrogen on the brain The molecular and metabolic effects of estrogen on brain function have been the subject of many review articles [5]. We refer to them, and present briefly the central view on the *
Corresponding author. Tel.: +358-2-2612-300; fax: +358-2-2612-340. E-mail address: [email protected] (R. Erkkola).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 4 7 5 - 7
46
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
Table 1 Literature review of studies on hormone replacement therapy in female postmenopause and cognitive functioning Refs. [7 – 25] Study
Study design
Subjects
Findings
Comment
[7]
unblinded, non-placebocontrolled nonrandomized trial, 6 months
no improvement in the four cognitive tests or mood measures
[8]
unblinded, non-placebocontrolled nonrandomized trial, 6 months
56 surgically menopausal (29 on ERT) and 32 hysterectomized women, aged 46 years 27 climacteric, aged 46 years, 26 postmenopausal women, aged 55 years, on ERT and progestin (1 month)
[9]
double-blind, placebocontrolled, randomized trial, 3 months
26 surgically or naturally menopausal women, aged 58 years; 11 on estriol, 15 on placebo
menopausal symptoms or education not adjusted for between the groups duration only 1 month, and effect of progestin, age and education not controlled; testing after five ‘‘wash-out’’ months may show learning effect effects of mood, menopausal symptoms or education controlled
[10]
double-blind, placebocontrolled, randomized trial, 6 months
18 surgically or naturally menopausal women, aged 29 – 68 years: nine on estrogen, nine on placebo
[11]
double-blind, placebocontrolled, randomized, cross-over trial, 4 months double-blind, randomized, cross-over trial, 3 months
64 peri- or postmenopausal women on estrogen and placebo
improvement on a self-rating memory scale during ERT vs. placebo
50 surgically menopausal women, aged 45 years, divided to five groups (three groups on HRT, one on placebo and one control)
improvement in all four tests used (Digit Span, verbal and visuomotor tests) during HRT vs. placebo
[12]
improvement in one of six cognitive tests after 1 month, and in all tests and mood scales after 6 months improvement on one alertness performance of nine cognitive tests in ERT group improvement in five of the six Guild memory subtests, compared with baseline in the estrogen group
estrogen and placebo groups were not compared; effects of age, mood, menopausal symptoms or education not controlled only self-rating was used; age and education not reported; menopausal symptoms not adjusted for the analyses were not adjusted for education, age, mood or menopausal symptoms
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
47
Table 1 (continued ) Study
Study design
Subjects
Findings
Comment
[13]
double-blind, placebocontrolled, randomized trial, 3 months
[14]
double-blind, placebocontrolled, randomized trial, 2 months prospective cohort, cognitive testing after 15 years of enrollment cross-sectional
36 surgically menopausal women, aged 53 years, two groups on estrogen and one on placebo 19 surgically menopausal women, aged 48 years; 10 on estrogen and nine on placebo 800 women: current (34% on ERT) past and non-estrogen users, aged 65 – 95 years 71 postmenopausal women, aged 55 and older, 39% on ERT with/without progestin
no improvement in the cognitive tests (Digit Span, Digit Symbol); depression improved improvement in one of four cognitive tests (paragraph recall) during estrogen no differences between the groups in MMSE, verbal or visual memory tests estrogen-users performed better in two of six verbal tests (paragraph recall measures) estrogen-users performed better on one of the two verbal memory tests administered estrogen-users ‘‘had better scores’’ on several verbal and nonverbal tests administered
the subjects were vasomotorically asymptomatic; the groups were not matched for education, and not compared the two groups were not matched for menopausal symptoms or education, and were not statistically compared the study was a part of a heart disease survey; age and education but not depression were adjusted for estrogen-users and nonusers were matched for age, but not for education or depression; progestin use not controlled; only verbal tests used estrogen-users and nonusers were matched for age and education, but not for progestin use and depression results or statistical comparisons not reported; the study groups were matched for age but not for education or depression ERT was evaluated 5 years before testing, only one test was used; age but not education or depression were adjusted for education but not depression was adjusted for analyses; only one cognitive test was administered
[15]
[16]
[17]
cross-sectional, case-control
72 postmenopausal women on ERT/HRT, and 72 nonusers, aged 55 – 93 years
[18]
cross-sectional
54 postmenopausal women, 39% on ERT with/without progestin, aged 50 and older
[19]
cross-sectional, case-control
214 women, mean age 80 years (21% on ERT)
no differences between the groups in Clock Drawing test
[20]
cross-sectional
288 postmenopausal women (40% on ERT), age of users 62 and nonusers 68 years
estrogen-users performed better on visual memory (BVR)
(continued on next page)
48
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
Table 1 (continued ) Study
Study design
Subjects
[21]
cross-sectional
15 ERT-users with/ without progestin, aged 65 years; 17 nonusers, aged 68 years
[22]
prospective cohort, community-based epidemiological study
727 women, mean age 74 years; 11% had used ERT
[23]
cross-sectional
14 ERT-users with/ without progestin; 41 non-users; age 65 and older
[24]
prospective cohort
9651 women, aged 65 and older; current, past and non-use of ERT was documented
[25]
A trial of estrogen effects using functional MRI
46 postmenopausal women, aged 33 – 61 years
Findings estrogen-users performed better on two memory tests (verbal and visual), but not on other 10 tests estrogen-users performed better in all four verbal tests
estrogen-users performed better on Digit-Span, but similarly to nonusers in other 12 cognitive measures current ERT users did not perform better on MMSE and the two visuomotor tests estrogen increased brain activation patterns differently during phases of working memory
Comment ERT use was not unopposed; the groups were matched on age and education, but not on depression
effect of age and education was controlled, but not effects of depression; the mean time since ERT was 25 years ERT-use was not unopposed; only one difference favored estrogen users in a comprehensive test battery effect of age, education and activity limitations were adjusted for; only three tests were administered the group was rather heterogeneous in relation to age and cause of menopause; estrogen had effects on working memory
mechanisms by which estrogen exerts its action on the brain and neurons. Estrogen receptors exist in several brain areas, including the cortex, hippocampus, amygdala, thalamus, hypothalamus, the basal forebrain and the preoptic area. These areas are involved in several cognitive functions; in particular, attention and memory. Although the precise action of estrogen in the brain is not clear, several mechanisms have been suggested. Estrogen induces the synthesis and activation of choline acetyltransferase, the rate-limiting enzyme in acetylcholine formation, as well as potassium-stimulated acetylcholine release in certain brain areas. By inducing the degradation of monoamine oxidase, estrogen enhances the activity of noradrenaline and dopamine in neural pathways involved in cognitive functions. Furthermore, estrogen regulates serotonin transport and binding in the brain. Estrogen upregulates dopamine receptors and interferes with catechol-Omethyltransferases, the enzyme catabolizing dopamine and noradrenaline. Although the exact nature of the estrogen effect on GABA is not completely clear, changes in both the release and re-uptake of GABA appear to be involved. Estrogen also has direct effects on neurons by stimulating axonal sprouting and dendritic spine formation. In hippocampal neurons, it increases dendritic spine density by reducing GABA neurotransmission. Evidence is also available to suggest that estrogen
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
49
could prevent neuronal atrophy. Estrogen may protect against cerebral ischemia by inducing central nervous system vasodilatation, slowing cerebral atherosclerosis and thus possibly preventing vascular dementia and other cognitive decline. Hence, there is a wealth of evidence making it biologically plausible to suggest the benefit of estrogen for brain function.
3. Effect of endogenous estrogen on cognition in postmenopausal women without HRT Yaffe et al. [6] studied the relationship between non-protein-bound or bioavailable estradiol and cognitive performance assessed with a modified Mini Mental Status Examination of women aged 65 or older. The testing was carried out at the baseline and after 6 years. The non-protein-bound and bioavailable estradiol were determined from the baseline-stored serum. Cognitive impairment occurs about three-fold more often in the lowest tertile in comparison with the highest tertile. In an earlier study, they did not find any benefit from the high total estradiol level.
4. Effects of HRT on cognition Previous studies on the effect of HRT/ERT on cognitive functions in samples of nondemented women have yielded conflicting results (Table 1, Refs. [7 –25]). The study methods were subjective questionnaires, semi-objective psychological tests and new methods with computer technology and based on the reaction time and the rate of mistakes made. Further, the lack of consistency between these studies has been attributed to other factors such as: small numbers of subjects recruited, differences in the estrogen preparations and their doses, the difference in the ages or the symptomatology of the subjects in the study populations, as well as the differences in the type of menopause (natural or surgical). Furthermore, there has frequently been a failure to distinguish between the effects of hormones on mood and depressive symptoms from an independent effect on cognition.
5. Own studies In our battery of studies, the following projects were carried out: (1) we investigated the effect of the severity of climacteric symptoms on cognitive functioning. Despite subjective complaints of memory impairment in association with climacteric vasomotor symptoms, our results did not support a direct cause- and effect relationship [26]. (2) In the second project, we designed a prospective, randomized, placebo-controlled, crossover study, whereby 70 healthy postmenopausal women were included. Three months’ estrogen replacement therapy (ERT) had no effect on cognitive functions. In that population, estrogen was not superior to placebo in any task of our comprehensive test battery. In those
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healthy and relatively young postmenopausal women, cognitive performance was well preserved. Observed cognitive changes were mild and primarily age-related, and not reversible by ERT ([26], Table 2). (3) In the third project, we compared two groups, one with an estrogen level of 25 –50 pmol/l (mean 43 pmol/l) and another with a higher estrogen level of 105 – 424 pmol/l (mean 249 pmol/l). Estrogen levels did not affect the cognitive performance ([28], Table 2). Table 2 Summary of own studies. The first study was a prospective, randomized, double-blinded, placebo-controlled cross-over study to investigate the effect of estrogen replacement therapy on the cognitive functions in postmenopausal women [27]. In the second study, subjects with a high estrogen level, either endogenous or exogenous, were compared with the subjects with low estrogen level [28] Test
Effect of ERT on cognition
Effect of estrogen concentration, (high vs. low)
Automatic processing Letters (six different targets) Numbers (four different targets) All targets
NS NS NS
NS NS NS
Reaction time tests SRT 2-CRT 10-CRT Subtraction test Verification test
NS NS NS NS NS
NS NS NS NS NS
Tests for controlled processing and working memory Subtraction time NS Verification time NS
NS NS
Attention Vigilance, reaction time Vigilance, errors Stroop
NS NS NS
NS high estrogen better NS
ND NS NS ND NS ND ND ND ND ND
NS NS NS NS NS NS NS NS NS NS
NS NS
NS NS
Verbal and nonverbal performances Similarities Digit Span Digit symbol Block design Benton visual retention test 20 objects naming time 20 objects immediate recall 20 objects delayed recall 30 PWA immediate recall 30 PWA delayed recall Auditorial verbal memory PASAT easy form PASAT difficult form
SRT = simple reaction time, CRT = choice reaction time, PWA = paired word associates, PASAT = paced auditory serial addition test, NS = nonsignificant, ND = not done.
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6. Conclusion Our studies of healthy postmenopausal women of 45 –65 years of age and computerbased cognition study methodology showed that the cognitive functioning was independent of severity of climacteric symptoms, estrogen therapy or estrogen level. Future studies on cognition in postmenopausal females should probably focus on older age groups, longer duration of treatment and patients with cognitive deterioration.
Acknowledgements Our studies received financial support from the Academy of Finland.
References [1] R. Erkkola, Female menopause, hormone replacement therapy, and cognitive processes, Maturitas 23 (1996) S27 – S30. [2] M. Hunter, R. Battersby, M. Whitehead, Relationships between psychological symptoms, somatic complaints and menopausal status, Maturitas 8 (1986) 217 – 228. [3] R. Erkkola, P. Holma, T. Ja¨rvi, S. Nummi, R. Punnonen, T. Raudaskoski, K. Rehn, M. Ryyna¨nen, P. Sipila¨, E. Tunkelo, A. Virkkunen, T. Virtavuo, O. Ylikorkala, Transdermal oestrogen replacement therapy in a Finnish population, Maturitas 13 (1991) 275 – 281. [4] A. Oldenhave, L.J. Jaszmann, A.A. Haspels, W.T. Everaerd, Impact of climacteric on well-being, A survey based on 5213 women 39 to 60 years old, Am. J. Obstet. Gynecol. 168 (1993) 772 – 780. [5] S.J. Birge, The role of ovarian hormones in cognition and dementia, Neurology 48 (Suppl. 7) (1997) S1 – S41. [6] K. Yaffe, L.-Y. Lui, D. Grady, J. Cauley, J. Kramer, S.R. Cummings, Cognitive decline in women in relation to non-protein-bound oestradiol concentrations, Lancet 356 (2000) 708 – 712. [7] L. Rauramo, K. Lagerspetz, P. Engblom, R. Punnonen, The effect of castration and peroral estrogen therapy on some psychological functions, Front. Horm. Res. 8 (1975) 133 – 151. [8] P. Fedor-Freybergh, The influence of estrogen on the wellbeing and mental performance in climacteric and postmenopausal women, Acta Obstet. Gynecol. Scand. (Suppl. 64) (1977) 1 – 91. [9] G. Vanhulle, R. Demol, A double-blind study into the influence of estriol on a number of psychological test in postmenopausal women, in: P.A. van Keep, R.B. Greenblatt, M. Albeaux-Fernet (Eds.), Consensus on Menopausal Research, MTP Press, London, 1976, pp. 94 – 99. [10] B.W. Hackman, D. Galbraith, Replacement therapy with piperazine oestrone sulfate (Harmogen) and its effects on memory, Curr. Med. Res. Opin. 4 (1976) 303 – 306. [11] S. Campbell, M. Whitehead, Oestrogen therapy and the menopausal syndrome, Clin. Obstet. Gynecol. 4 (1977) 31 – 47. [12] B.B. Sherwin, Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women, Psychoneuroendocrinology 13 (1988) 345 – 357. [13] E.C. Ditkoff, W.G. Crary, M. Cristo, R.A. Lobo, Estrogen improves psychological function in asymptomatic postmenopausal women, Obstet. Gynecol. 78 (1991) 991 – 995. [14] S.M. Phillips, B.B. Sherwin, Effects of estrogen on memory function in surgically menopausal women, Psychoneuroendocrinology 17 (1992) 485 – 495. [15] E. Barrett-Connor, D. Kritz-Silverstein, Estrogen replacement therapy and cognitive function in older women, JAMA 269 (1993) 2637 – 2641. [16] D.L. Kampen, B.B. Sherwin, Estrogen use and verbal memory in healthy postmenopausal women, Obstet. Gynecol. 83 (1994) 979 – 983. [17] D. Robinson, L. Friedman, R. Marcus, J. Tinklenberg, J. Yesavage, Estrogen replacement therapy and memory in older women, J. Am. Geriatr. Soc. 42 (1994) 919 – 922.
52
R. Erkkola, P. Polo-Kantola / International Congress Series 1229 (2002) 45–52
[18] D. Kimura, Estrogen replacement therapy may protect against intellectual decline in postmenopausal women, Horm. Behav. 29 (1995) 312 – 321. [19] A. Paganini-Hill, V.W. Henderson, The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women, J. Am. Geriatr. Soc. 44 (1996) 818 – 822. [20] S.M. Resnick, J. Metter, A.B. Zonderman, Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology 49 (1997) 1491 – 1497. [21] S.M. Resnick, P.M. Maki, S. Golski, M.A. Kraut, A.B. Zonderman, Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance, Horm. Behavior 34 (1998) 171 – 182. [22] D.M. Jacobs, M.-X. Tang, Y. Stern, M. Sano, K. Marder, K.L. Bell, P. Schofield, G. Dooneief, B. Gurland, R. Mayeux, Cognitive function in nondemented older women who took estrogen after menopause, Neurology 50 (1998) 368 – 373. [23] L.E. Carlson, B.B. Sherwin, Steroid hormones, memory and mood in a healthy elderly population, Psychoneuroendocrinology 23 (1998) 583 – 603. [24] K. Matthews, J. Cauley, K. Yaffe, J.M. Zmuda, Estrogen replacement therapy and cognitive decline in older community woman, J. Am. Geriatr. Soc. 47 (1999) 518 – 523. [25] S.E. Shaywitz, B.A. Shaywitz, K.R. Pugh, R.K. Fulbright, P. Skudlarski, W.E. Mencl, R.T. Constable, F. Naftolin, S.F. Palter, K.E. Marchione, L. Katz, D.P. Shankweiler, J.M. Fletcher, C. Lacadie, M. Keltz, J.C. Gore, Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks, JAMA 281 (1999) 1197 – 1202. [26] P. Polo-Kantola, R. Portin, T. Koskinen, O. Polo, K. Irjala, R. Erkkola, Climacteric symptoms do not impair cognitive performances in postmenopause, Maturitas 27 (1977) 13 – 23. [27] P. Polo-Kantola, R. Portin, O. Polo, H. Helenius, K. Irjala, R. Erkkola, The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women, Obstet. Gynecol. 91 (1998) 459 – 466. [28] R. Portin, P. Polo-Kantola, O. Polo, T. Koskinen, A. Revonsuo, K. Irjala, R. Erkkola, Serum estrogen level, attention, memory and other cognitive functions in middle-aged women, Climacteric 2 (1999) 115 – 123.