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Sex Steroid Hormones and Memory

Sex Steroid Hormones and Memory. April 3, 2001. Talk Outline. The menstrual cycle and the key hormones The pill Estrogen and its effects on the body Estrogen and memory – research and clinical implications Estrogen and men??? Testosterone and memory? Estrogen and Alzheimer’s Disease.

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Sex Steroid Hormones and Memory

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  1. Sex Steroid Hormones and Memory April 3, 2001

  2. Talk Outline • The menstrual cycle and the key hormones • The pill • Estrogen and its effects on the body • Estrogen and memory – research and clinical implications • Estrogen and men??? • Testosterone and memory? • Estrogen and Alzheimer’s Disease

  3. Estrogen’s Effects • Reproductive system • Cardiovascular system • Bones • Brain

  4. Estrogen – the Basics • It is a steroid hormone that comes from the following link: • Cholesterol  Pregnelone  DHEA  Adrostendione  Testosterone  Estrogen • Major part produced in the ovaries (95%) • The adrenals and the brain can produce estrogen as well

  5. 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)

  6. The Menstrual Cycle • Usually 28 days (ranging from 21 to 35 or more) • First day of cycle is the first day of menstruation

  7. The HPG Axis

  8. Menstrual Cycle – FSH and LH

  9. The Menstrual Cycle - II

  10. The Menstrual Cycle - III

  11. The Menstrual Cycle - V

  12. When We Take the Pill

  13. 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?

  14. Estrogen and Menopause What happens to estrogen as we age?

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

  16. Testosterone and Aging

  17. 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

  18. Estrogen and the Brain A two-fold increase in dendritic spines produced by a single dose of estrogen in rat’s embryo cells

  19. To Study the Effects of E We Can: • Remove E and supplement it in a controlled fashion • Take a population that is already lacking E • Measure variations of endogenous E levels and compare performance (i.e., low E vs. high E) • Compare E users vs. non-users (post-menopausal women)

  20. Experimental Paradigms • Estrogen and animals • Estrogen and normal young women • Estrogen and clinical populations • Estrogen and transsexual populations • Estrogen and postmenopausal women • Estrogen and men • Estrogen and dementia

  21. Animal research • Many studies show that ovariectomized rats do worse on water maze test as compared to normal animals • Replacing E endogenously leads to improvement in memory • Also, giving E to old rats leads to better performance

  22. Estrogen and Pre-menopausal Women • Compare performance at different times throughout the cycle

  23. 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

  24. 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

  25. However… • 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)

  26. 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

  27. 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

  28. Clinical Populations • Women with uterine myomas • Sherwin & Tulandi (1996) • Baseline assessment of 19 women • Suppressed GnRH with Lupron (GnRH agonist) for 12 weeksand measured cognitive performance • Divided Ss into two groups and gave E to one half and Placebo to the second

  29. A Reminder… • Lupron is a GnRH • agonist • No sex steroids are • being produced

  30. Sherwin & Tulandi – the Design • BASELINE • Test #1 • Lupron treatment 12 weeks • Test #2 • Lupron +Pl or Lupron + E • Test #3

  31. 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 • After treatment, the Lupron + E group and not the Lupron + Pl had increased scores • THE PERFECT STUDY!

  32. If Lupron is so great, why aren’t there more studies using this paradigm? • My present research and Lupron

  33. Other Clinical PopulationsWomen 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 PAT of untreated women decreased;

  34. TranssexualsMen Changing to Women • Miles et al., 1998 – men on E had higher PAL scores (paired associate learning) • 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

  35. Post-menopausal Women • Huge number of studies showing  in verbal memory in women on ERT • 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 ERT is estrogen plus progesterone (opposing)

  36. However… • In well controlled studies, E increases scores of verbal memory • Kantor (1975) – 25, 75-years-old women received E and 25 placebo • Scores of E group increases over the first 18 months • Scores of P decreased • Kampen & Sherwin* (1992) – E users performed better on immediate and delayed paragraph recall as compared to non-users (well-matched groups)

  37. More Studies… Negative findings: • Ditkoff et al (1991) – two doses of E and PL; Digit symbol & Digit span tests were the only measures – no differences

  38. Summary • E is exerting positive effect on short and long term verbal memory and mood in women • It might have detrimental effects in visual-spatial memory in women • ? Tests administered (some only self-report) • ? E plasma levels not measured in all studies • ? Interactions with other drugs

  39. 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 • Keenan et al (2001) + FL and WM • Future directions • More controlled studies • fMRI, PET, EEG

  40. 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 5-alpha-reductase Aromatase enzyme VERY HARD TO DISTINGUISH BETWEEN THE EFFECTS OF E OR T!

  41. Going back to the transsexual studies… • E increased scores on tests of verbal memory in men taking E, while their spatial skills decreased

  42. Estrogen and AD - I The AD Brain Normal  Moderate  Severe 

  43. Biological Plausibility of E • Promoting survival of ACh neurons via estrogen-neurotrophin interactions • Reducing the toxicity of amyloid α-peptide on hippocampal neurons • E can blunt stress-induced and AD-related elevation of glucocorticoids • E can have an antioxidant effect • Lower blood pressure and enhance cerebral blood flow and vascular reactivity • E enhances neurotransmitter synthesis and function

  44. 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

  45. Estrogen and AD III • However… • Results show that it can prevent or delay 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

  46. Estrogen and AD - III • Estrogen might be reducing the risk of developing AD Again, take this with a grain of salt – we cannot control the variables!

  47. Testosterone and Cognition • Testosterone also declines as we age • So, does this reduction affect cognition?

  48. 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

  49. 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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