Menopause and Cognition

1
Menopause and Cognition

• Regan Theiler, MD, PhD

2
Perimenopausal Transition

• Average age of onset 46 (39-51)
• Average duration 5 years (2-8)
• Menstrual cycle irregularity
• Hot flushes

3
Menopause

• Permanent cessation of menses (1 year)
• Average age of 51 years (45-55)
• Beginning of increased risk for
• Osteoporosis
• CAD
• Stroke
• Alzheimers dementia

4
(No Transcript)
5
Menopausal Symptoms

• Hot flushes (50-90)
• Sleep disturbances
• Vaginal dryness and atrophy
• Mood changes
• Cognitive changes

6
Hormonal Changes
Pre-menopause
Post-menopause
7
Estrogen Loss and Manifestations of Health Risks
Over Time
Estrogen Secretion
40
45
50
55
60
65
70
?75
Age (years)
8
Cognitive Changes

• Verbal memory
• Non-verbal memory
• Attention span
• How to measure clinically significant changes?
• Surgical vs. natural menopause

9
Artificial Menopause

• Oophorectomy
• GnRH agonists
• Associated with severe hot flushes
• Possible association with cognitive changes

10
Oophorectomy and Memory

• 19 women, average 48 y.o.
• TAH/BSO, benign indications
• Randomized to CEE replacement or placebo for 8
  weeks
• Decline in memory scores from baseline in placebo
  group (P

11
Correlation of Hot Flush Frequency With Memory
2 Months After Bilateral Ovariectomy
Measure
R Value
P Value
Immediate paired-associate recall scores Delayed
paired-associate recall scores

0.43 0.39
n 19.Hot flushes were negatively correlated
with immediate and delayed paired-associate
recall scores. R correlation coefficient. Philli
ps SM, Sherwin BB. Psychoneuroendocrinology.
199217485-95.
12
Lupron Estrogen Trial

• 19 women, ave. 34 y.o. with leiomyomas
• Lupron for 12 weeks
• Randomized to add-back CEE or placebo plus Lupron
  for 8 weeks
• Cognitive testing using Wechsler memory scale
  pre- and post-treatment

Sherwin and Tulandi. J Clin Endocrinology and
Metabolism, 1996.
13
Wechsler Memory Scale Scores


P
14
Results

• Significantly decreased scores after 12 weeks
  Lupron
• CEE replacement arm improved to baseline memory
  score
• Significantly better performance than placebo arm
  after 8 weeks CEE
• Similar to studies of women after oophorectomy

15
Natural Menopause and Cognition
16
Baltimore Longitudinal Study on Aging

• 116 women taking HRT, duration 6 mos-20 years.
  Average age 61 yr.
• 172 women not taking HRT. Average age 67 yr.
• Matched for education level, vocabulary, health
  and socioeconomic status
• Tests of verbal and visual memory with 6 yr.
  follow up

Resnick and Maki. Ann. New York Acad Sciences,
1996.
17
Benton Visual Retention Test
Age-matched, initiation between time 1 and time 2
Age-adjusted
Resnick and Maki. Ann. New York Acad Sciences,
1996.
18
California Verbal Learning Test
Resnick and Maki. Ann. New York Acad Sciences,
1996.
19
ERT/HRT Affects Cerebral Blood Flow in Women
During Performance of Memory Tests
Mean Age, 65 Years
Verbal Memory
Figural Memory
R Inferior Frontal
R Para-hippocampal
R Para-hippocampal
R Inferior Parietal
Areas highlighted by crosshair indicate regions
of altered activation for women taking ERT/HRT.
n 32. Resnick SM, et al. Horm Behav.
199834171-82.
20
ERT/HRT Users Show Significant Increases in Blood
Flow in the Hippocampus Over a 2-Year Interval
R
GreaterEffect
R
L
L
Areas in color show the brain regions where
women receiving ERT/HRT showed increased blood
flow over time compared with women not
receiving ERT/HRT.
R
L
Blue arrow points to the hippocampus
Maki PM, Resnick SM. Neurobiol Aging.
200021373-83.
21
Baltimore Longitudinal Study

• Current users of HRT score higher on visual and
  verbal memory testing
• Initiation of HRT associated with preservation of
  memory over 6 years
• Increased blood flow to memory centers in women
  using HRT
• HRT users less likely to develop Alzheimers
  dementia

22
Can HRT prevent or treat dementia?
23
ERT/HRT Use and AD Risk
Heyman et al, 1984 Amaducci et al, 1986 Broe et
al, 1990 Graves et al, 1990 Brenner et al,
1994 Henderson et al, 1994 Paganini-Hill
Henderson, 1994 Mortel Meyer, 1995 Baldereschi
et al, 1998 Waring et al, 1999 Slooter et al,
1999 Tang et al, 1996 Kawas et al, 1997 Yaffe et
al, 1998 LeBlanc et al, 2001
Relative Risk (95 CI)
Adapted from LeBlanc ES, et al. JAMA.
20012851489-99.
24
ERT/HRT and Alzheimers Disease

• ERT/HRT use is associated with reduced risk or
  delayed onset of AD1-3
• Dose-dependent effect, i.e. longer therapy is
  more protective
• Estrogen probably does not improve AD symptoms or
  progression5,6

1Kawas C, et al. Neurology. 1997481517-21. 2
Paganini-Hill A, Henderson VW. Arch Intern Med.
19961562213-7. 3Tang M-X, et al. Lancet.
1996348429-32. 5Henderson VW, et al. Neurology.
200054295-301. 6Mulnard RA, et al. JAMA.
20002831007-15.
25
Observational vs Randomized Studies
HT and AD

• Observational Prospective Studies
• Typical patterns of HT use (age, treatment)
• Mostly E alone
• ? Risk for AD

• Womens Health Initiative Memory Study (WHIMS)
• Only women ?65 years of age
• CEE MPA
• ? Risk of all-cause dementia

26
Womens Health Initiative Memory Study (WHIMS)

• Ancillary study to the WHI, a randomized,
  multicenter study of CEE alone and CEE plus MPA
• Primary outcome measure probable dementia
• Two studies from WHIMS have been published
• Effect of CEE/MPA on probable dementia and mild
  cognitive impairment1
• Effect of CEE/MPA on global cognitive function2

1Shumaker SA, et al. JAMA. 20032892651-62. 2Rapp
SR, et al. JAMA. 20032892663-72.
27
WHIMS Dementia and Mild Cognitive Impairment

• 4532 postmenopausal women with a uterus and free
  of probable dementia, aged ?65 years, were
  recruited from WHI centers and enrolled in the
  EP arm of the WHIMS1
• Study drug administration was stopped early
• Mean time between randomization and last 3MSE in
  WHIMS was 4.05 years
• The ending of the CEE-only component of WHI and
  WHIMS 1 year before its planned completion was
  announced by the NIH on March 2, 2004

1Shumaker SA, et al. JAMA. 20032892651-62.
28
Cases of Probable Dementia and Mild Cognitive
Impairment
Shumaker SA, et al. JAMA. 20032892651-62.
29
Cumulative HR for a Diagnosis of Mild Cognitive
Impairment
HR, 1.07 95 CI, 0.741.55
Number of Events CEE/MPA 5 18 18 11 4 Placebo 7
8 18 12 6
Shumaker SA, et al. JAMA. 20032892651-62.
30
Cumulative HR for a Diagnosis of Probable Dementia
HR, 2.05 95 CI, 1.213.48
Number of Events CEE/MPA 5 7 8 11 4 Placebo 3 2
3 3 9
Shumaker SA, et al. JAMA. 20032892651-62.
31
Classification of Probable Dementia Cases by
Treatment Assignment
Shumaker SA, et al. JAMA. 20032892651-62.
32
One-Year Change in Other QOL-Related Measures
Depression Sleep Disturbance Satisfaction With
Sex mMMSE

0
0
Change From Baseline at Year 1
For all parameters except depression, higher
numbers indicate a positive effect and lower
numbers indicate a negative effect. P compared with placebo at Year 1. Hays J, et al. N
Engl J Med. 20033481839-54.
33
WHIMS Conclusions

• In asymptomatic women 65 years of age at
  randomization
• Combined HRT increased the risk of dementia from
  all causes
• HRT did not change rate of mild congnitive
  impairment as measured by mMMSE
• Long-term data not yet available

34
Summary

• Surgical and natural menopause may be associated
  with memory changes
• Early HRT may prevent development of memory
  deficits after artificial menopause
• Menopausal HRT may prevent later Alzheimers
  dementia
• HRT may increase the risk of vascular dementia
• Late HRT or HRT after dementia onset does not
  prevent or improve symptoms

35
Recommendations

• NIH Consensus Conference (2005)
• There is insufficient information to conclude
  that there is any causal relationship between the
  menopausal transition and difficulty thinking,
  forgetfulness, or other cognitive disturbances.
• NIH State of the Science Panel. Ann Internal
  Medicine. June 21, 2005.

36
(No Transcript)
37
The American Gyencological Journal, 1892