Sex Steroid Hormones and Memory

April 3, 2001

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

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

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)

Estrogen’s Effects

• Reproductive system

• Cardiovascular system

• Bones

• Brain

The Menstrual Cycle

• Usually 28 days (ranging from 21 to 35 or more)

• The first day of menstruation marks the beginning of a cycle

Hormones and glands

• GnRH• LH• FSH• Estrogen• Progesterone

The HPG Axis

Menstrual Cycle – FSH and LH

The Menstrual Cycle - II

The Menstrual Cycle - III

The Menstrual Cycle - V

When We Take the Pill

Estrogen and Menopause

What happens to estrogen as we age?

Andropause???

•What is happening to males sex hormones over the lifespan?

Testosterone and Aging

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?

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

Estrogen and the Brain

A two-fold increase in dendritic spines produced by a single dose of estrogen in rat’s embryo cells

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)

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

Estrogen and Pre-menopausal Women

• Compare performance at different times throughout the cycle

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

A Reminder…

-Lupron is a GnRH antagonist

-No sex steroids are being produced

Sherwin & Tulandi – the Design

• BASELINE – Test #1

• Lupron treatment 12 weeks– Test #2

• Lupron +Pl or Lupron + E– Test #3

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!

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;

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

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

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

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)

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)

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

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)

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

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)

• More research is needed…

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

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

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!

Estrogen and AD - I The AD Brain

Normal

Moderate

Severe

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

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

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

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!

Testosterone and Cognition

• Testosterone also declines as we age

• So, does this reduction affect cognition?

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

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…

Testosterone

• So, does it affect cognition?

• Possibly yes …but it is hard to show it

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?

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…