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Sex Steroid Hormones and Memory
April 3, 2001
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Talk Outline
• Estrogen and its effects on the body• The menstrual cycle and the key hormones• The pill• Estrogen and memory – research and clinical
implications• Estrogen and men???• Testosterone and memory?• Estrogen and Alzheimer’s Disease
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Estrogen – the Basics
• Major part produced in the ovaries (95%)
• It is produced in the adrenals and the brain by conversion
• It is a steroid hormone that comes from the following link:
• Cholesterol Pregnelone DHEA Adrostendione Testosterone Estrogen
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Estradiol – Estrone – Estriol
• Estradiol (E2) is the main one• 25% of E2 is converted to estrone (E1)• A small amount of estradiol is converted to
estriol• E receptors have highest affinity for E2 and
lowest for estriol• There are two major types of E receptors:
– ERα and ERβ (Eβ2)
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Estrogen’s Effects
• Reproductive system
• Cardiovascular system
• Bones
• Brain
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The Menstrual Cycle
• Usually 28 days (ranging from 21 to 35 or more)
• The first day of menstruation marks the beginning of a cycle
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Hormones and glands
• GnRH• LH• FSH• Estrogen• Progesterone
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The HPG Axis
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Menstrual Cycle – FSH and LH
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The Menstrual Cycle - II
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The Menstrual Cycle - III
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The Menstrual Cycle - V
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When We Take the Pill
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Estrogen and Menopause
What happens to estrogen as we age?
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Andropause???
•What is happening to males sex hormones over the lifespan?
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Testosterone and Aging
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How Did It All Start?
• Age-related cognitive declines• Estrogen depletion after menopause• Estrogen replacement therapy
• It’s clear that E can modulate brain physiology but… how can we examine the role of estrogen as a modulator of behaviour?
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Estrogen and the Brain There are many physiological
mechanisms through which E can exert effects:
• Genomic and non-genomic action
• Estrogen receptors in the brain
• Estrogen and neurotransmitter systems (Ach, Na)
• Effect of estrogen on dendritic spines
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Estrogen and the Brain
A two-fold increase in dendritic spines produced by a single dose of estrogen in rat’s embryo cells
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To Study the Effects of E We Can:
1. Take advantage of variations of endogenous E levels and compare performance (i.e., low E vs. high E)
2. Remove E and supplement it in a controlled fashion
3. Give E to a population that is already lacking it
4. Compare E users vs. non-users (post-menopausal women)
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Estrogen and Pre-menopausal Women
• Hapmson (1990, 1992) + + + • Phillip & Sherwin (1995) + + +• Gordon & Lee (1993) - - -
???• Huge variations in results most likely
due to:– Use of different tests– Estrogen levels remain relatively
high – Role of Progesterone is unclear
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Estrogen and Pre-menopausal Women
• Compare performance at different times throughout the cycle
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Pre-menopausal women• Women with uterine myomas
• Sherwin & Tulandi (1996)
– Baseline assessment of 19 women– Suppressed GnRH with Lupron (GnRH
antagonist) for 12 weeks and measured cognitive performance
– Divided Ss into two groups and gave E to one half and Placebo to the second
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A Reminder…
-Lupron is a GnRH antagonist
-No sex steroids are being produced
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Sherwin & Tulandi – the Design
• BASELINE – Test #1
• Lupron treatment 12 weeks– Test #2
• Lupron +Pl or Lupron + E– Test #3
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Sherwin and Tulandi III• Results:
• All sex hormones decreased after Lupron
• Only E increased when E was added back
• Scores on neuropsychological tests of verbal memory decreased after Lupron
• The Lupron + E group and not the Lupron + Pl had increased scores on the same tests
• THE PERFECT STUDY!
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Other Clinical Populations Women with removed ovaries
• No gonadal production of sex hormones• They have to have HRT (to prevent early
osteoporosis) memory, mood, overall sense of well being• Phillip & Sherwin – tested women before surgery
(THA) and after 3 months of treatment with E; – baseline neuropsych scores DID NOT differ– scores on immediate and delayed recall of PAL of
untreated women decreased;
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Estrogen and Progesterone
• HRT is usually both E and Progesterone (P)• How does P affect cognitive functioning
(knowing that P opposes the effects of E)• Rice et al. (2000) looked at 837 older
Japanese women• E or E+P or Placebo• E led to increase in performance• E+P and Placebo decrease in performance
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Negative Effects of E?
• Men excel in tasks involving spatial abilities
• Women are better at fine-motor tasks and verbal abilities
• These differences are subtle but present
• Hormones (estrogen testosterone) appear to be responsible for these differences
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Negative Effects of E II
• Hausmann et al (2000) – 12 pre-menopausal women; measured performance on 3 spatial test during the cycle
• Scores were higher when E was low and T was high (Mental Rotation task)
• T has positive influence on Mental Rotation task• E has negative influence on the same task
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So what’s so special about Estrogen?
• Two meta-analyses show that E does influence cognitive functioning but the effects are small and it is easy to “miss” them
• Janowski et al (2001)
• Hogervorst et al (2000)
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Transsexuals Men Changing to Women
• Van Goozen, 1995 – mental rotation was impaired (males excel) and verbal fluency improved (women excel) in men taking estrogen; – The opposite was true for women– Able to reverse the effects when HRT was terminated
• Miles et al., 1998 – men on E had higher PAL scores (paired associate learning)
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Post-menopausal women I
To study effects of E in this population we can:
• Cross-sectional design (E users vs. non-users)
• Prospective studies – E or Pl is administered and memory measured at baseline and following treatment
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Post-menopausal women II
• In well controlled studies, increase in performance on verbal memory tests is documented when E is given to Ss
• Kantor (1975) – 25, 75-years-old women received E and 25 placebo– E group showed over the first 18 months– Placebo group showed
• Kampen & Sherwin* (1992) – E users performed better on immediate and delayed paragraph recall as compared to non-users (well-matched groups)
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More Studies…
Negative findings:
• Ditkoff et al (1991) – two doses of E and PL; – Digit symbol & Digit span test were
the only measure –– found no differences between
groups
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Post-menopausal women III• Large number of studies showing
in verbal memory following E suplimentaon (either experimental or HRT)
• Again, there is inconsistency in findings
• Most likely due to different testing procedure and/or type of estrogen used
• Findings are even more complicated when HRT is comprised of E plus P (opposing)
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• More research is needed…
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Summary• Positive effect on short and long term verbal
memory and mood in women• It might have detrimental effects in visual-
spatial memory in women• ? Differences in experimental tests • ? Differences in E preparations and
therapies• ? E levels in plasma not measured in all
studies • ? Interactions with other drugs
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How Exactly E Affects Performance?
• “Hippocampal” theory– McEwen et al (1999) – fMRI, E and hippocampal
volume• Working memory and E???
– Hapmson et al (2000) +– Janowski et al (2000) + men; - women (abstract
stimuli)– Shaywitz et al (1998) fMRI study
• Future directions– More controlled studies– fMRI, PET, EEG
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Estrogen and Men?
• If it was complicated for women – it’s even more for men…
• E is produced in the male’s brain • Testosterone is converted to DHT or E
TESTOSTERONE
DHT E
Aromatase enzyme5-alpha-reductase
VERY HARD TO DISTINGUISH BETWEEN THE EFFECTS OF E OR T!
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Estrogen and AD - I The AD Brain
Normal
Moderate
Severe
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Biological Plausibility of E 1. Promoting survival of ACh neurons via estrogen-
neurotrophin interactions2. Reducing the toxicity of amyloid -peptide on
hippocampal neurons3. E can blunt stress-induced and AD-related
elevation of glucocorticoids4. E can have an antioxidant effect5. Lower blood pressure and enhance cerebral
blood flow and vascular reactivity6. E enhances neurotransmitter synthesis and
function
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Estrogen and AD II• The list is impressive…But can it cure AD?
• Wang et al (2000) – 50 females with AD– 1/2 on E and 1/2 on placebo– Non-significant results
• Hogervorst et al (2000) – The Oxford meta-analysis of E,cognition and AD – Suggested that E does have a protective function
against development of clinically diagnosed AD
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Estrogen and AD III
• Most likely it delays the the onset of AD in women who are taking ERT
• Some studies show slight improvements in *mildly demented patients* taking E, but nothing sure yet
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Estrogen and AD - III
• Estrogen might be reducing the risk of developing AD
Again, take this with a grain of salt – we cannotcontrol the variables!
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Testosterone and Cognition
• Testosterone also declines as we age
• So, does this reduction affect cognition?
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Testosterone and Cognition II• Binding sites are found in
the hypothalamus, amygdala, diencephalic nuclei
• May be the effects are mediated by E (converted)
• T improves mood and sense of well being
• Some research on cognitive performance
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Testosterone and Cognition III
• Janowski et al (1994, 2000) found that T influences spatial cognition (male dominated) and WM tasks
• Van Goozen (1995) – female to male transsexuals on T showed visuospatial performance and scores on verbal tasks (female dominated)
• A lot more studies are needed…
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Testosterone
• So, does it affect cognition?
• Possibly yes …but it is hard to show it
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Mass HRT Administration???
• Beneficial effects of HRT– Cardiovascular health (E)– Bone maintenance (E)– Cognition (E) (T?)
• Drawbacks of HRT– Breast and uterine cancer (E)– Prostate cancer (T)
•Is HRT the solution for memory deficits?
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Last Words• Hormones do play a major role in age-
related cognitive changes• We know more about E than any other
one• Research is needed for T and P• HRT should be given with caution
especially in men (T)• Don’t leave this room thinking that
estrogen can do it all … rather think that it might be part of the solution…
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