Triad 5: with Triad 2 The of Sex Hormones and Brain Health ...glvhealth.com/LargeFiles/Mod 20b CD/1 Slide Color/4A - Triad 5 and... · The Role of Sex Hormones and Brain Health Pamela

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Triad 5: Stacking with Triad 2The Role of Sex Hormones and Brain Health

Pamela W. Smith, M.D., MPHThe following potential conflict of interest relationships are

germane to my presentation.

Equipment: NoneSpeakers Bureau: PCCA, Spectracell, ZRT & Orthomolecular

Stock Shareholder: NoneGrant/Research Support: None

Consultant: CustomVite, Pathway & Thorne

Status of FDA devices used for the material being presented NA/Non‐Clinical

Status of off‐label use of devices, drugs or other materials that constitute the subject of this presentation: NA/Non‐Clinical

Triad 5: Stacking with Triad 2The Role of Sex Hormones and Brain

Health

Pamela W. Smith, M.D., MPH

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Copyright © 2012 James B. LaValle, Integrative Health Resources, LLC. All rights reserved. No part of this material may be used or reproduced in any manner whatsoever, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the author.

This material is provided for educational and informational purposes only to licensed health care professionals. This information is obtained from sources believed to be reliable, but its accuracy cannot be guaranteed. Herbs and other natural substances are very powerful and can occasionally cause dangerous allergic reactions in a small percentage of the population. Licensed health care professionals should rely on sound professional judgment when recommending herbs and natural medicines to specific individuals. Individual use of herbs and natural medicines should be supervised by an appropriate health care professional. The use of any specific product should always be in accordance with the manufacturer's directions.

Reference• Bassil, N., et al.., “Endocrine aspects of healthy brain aging,” in Desai, A., (Ed.) Healthy Brain Aging: Evidence Based Methods to Preserve Brain Function and Prevent Dementia, 2010; 26(1):57‐74.

• Smith, P., What You Must Know About Women’s Hormones. Garden City Park, NY: Square One Publishing, 2010.

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Pregnenolone and Memory

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Pregnenolone

• Precursor to DHEA, estrogen, progesterone, testosterone, and cortisol.

• Is made from cholesterol.– If the total cholesterol goes below 140 then pregnenolone is not as effectively made.

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Pregnenolone (Cont.)

• Decreases with age– At age 75, most people have a 65% decline compared to age 35.

• Akwa, Y., et al., “Neurosteroids: biosynthesis, metabolism, and function of pregnenolone and dehydroepiandrosterone in the brain,” Jour Steroid Biochem Mol Biol 1991; 40(1‐3):71‐81.

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• Regulates the balance between excitation and inhibition in the nervous system

• Increases resistance to stress• Improves energy both physically and mentally• Enhances nerve transmission and memory• Modulates NMDA receptors

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Pregnenolone and Memory (Cont.)

• Directly influences acetylcholine release• Reduces pain and inflammation• Blocks the production of acid‐forming compounds

• Promotes new nerve growth factor• Modulates GABA• Helps to repair nerve damage• Improves sleep

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References

– Mayo, W., et al., “Pregnenolone sulfate enhances neurogenesis and PSA‐NCAM in young and aged hippocampus,” Neurobiol Aging 2005; 2691):103‐14.

– Mayo, W., et al., “Individual differences in cognitive aging: implication of pregnenolone sulfate,” Prog Neurobiol 2003; 71(1):43‐8.

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Causes of Low Pregnenolone

• Aging process• Eating too much saturated fat and trans‐fats• Low cholesterol levels• Hypothyroidism• Pituitary tumor• Having a severe illness

– Pregnenolone will make more cortisol and less of the other hormones to help with stress.

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Symptoms of Pregnenolone Deficiency

• Arthritis• Depression• Fatigue• Inability to deal with stress• Insomnia• Lack of focus• Memory decline

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• Like all hormones, pregnenolone levels must be measured before giving the hormone.

• Start with pregnenolone 10 mg SR. • Repeat levels in 90 days.

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Possible Side Effects of Pregnenolone Use• Acne• Drowsiness• Muscle aches• Fluid retention• Headache• Heart racing• Insomnia due to overstimulation• Irritability, anger, anxiety

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Sex Hormones and Memory

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Reference

– Polcz, T., et al., “Effects of estrogen and progesterone on the central nervous system,” in Fraser, I., et al., (Eds.) Estrogens and Progestogens in Clinical Practice. New York: Churchill Livingstone, 2000.

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• Sex hormones and their metabolites have many actions on the brain.

• Sex hormones have direct and indirect effects on neurons, glia, and vessels.

• The effects require steroid receptor‐mediated gene expression, transcription, and translation which may take days to result in changes.– Ibid., Polcz

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Sex Hormones and Memory (Cont.)

• Other effects of sex hormones act directly on ion channels and take seconds to minutes to activate a change when they are coupled to second messengers and to the early‐intermediate genes.– CFOs– Jun

• Ibid., Polcz.

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Effects of Sex Hormones on Neurons

• Delayed action: genomic response mediated by steroid receptor.– Estrogen and progesterone

• Nerve growth and differentiation• Modulation of intramembranous protein particles• Cytoarchitectural changes• Synaptologic changes in hypothalamus

– Ibid., Polcz.

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Effects of Sex Hormones on Neurons (Cont.)

• Delayed action: genomic response mediated by steroid receptor

• Estrogen• Increased choline acetyl transferase synthesis• Stimulates neuronal NO synthase• Increased degradation of monoamine oxidase• Increased number of NMDA sensitive receptors in hippocampus

– Ibid., Polcz.21


• Intermediate action: involves second messenger systems or early intermediate genes (e.g., c‐Fos, Jun)– Estrogen

• Increased G‐protein coupled cAMP dependent kainate‐induced ion current in CA1 neurones

– Ibid., Polcz.

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• Rapid action: direct action on cell membrane (e.g., Ion channel, synaptic transmitters) – Estrogen

• Modulation of dopamine receptor binding in striatum• Increased K+ permeability of postsynaptic membrane in amigdala neurones

• Postsynaptic potentiation of non‐MNDA receptors in CA1 neurones

• Calcium transport mechanism in nerve endings– Ibid., Polcz. 23


• Rapid action: direct action on cell membrane (e.g., Ion channel, synaptic transmitters)– Progesterone

• Stimulates release of dopamine in striatal tissue• Stimulates release of GnRH from hpothalamic neurones• Modulation of oxytocin receptor binding in the hypothalamus

– Ibid., Polcz.

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• Rapid action: direct action on cell membrane (e.g., Ion channel, synaptic transmitters) (cont.)– Progesterone (cont.)

• Inhibition of opioid receptor binding• Potentiation of GABA• Direct incorporation of steroids in cell membrane?

– Ibid., Polcz.

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• Pregnenolone, pregnenolone sulfate, progesterone, allopregnanolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and estradiol all have modulatory effects on the release of neurotransmitters.

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Reference

– Zheng, P., “Neuroactive steroid regulation of neurotransmitter release in the CNS: action, mechanism and possible significance,” Prog Neurobiol 2009; 89(2):134‐52.

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• The neurotransmitters affected by memory include– Glutamate– GABA– Acetylcholine– NE– Dopamine– 5‐HTP

• Ibid., Zheng.28


• Many of the effects of these neurotransmitters occur in areas of the brain involved in learning and memory, emotion, motivation, motor, and cognition.– Ibid., Zheng.

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• The mechanisms of affect of the neurotransmitters are complicated.

• Numerous involve rapid non‐genomic effects on presynaptic receptors and ion channels. – Ibid, Zheng.

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• Presynaptic receptors and ion channels that may be affected– Sigma‐1 receptor– Alpha(1) receptor– Nicotine receptor– D1 receptor– NMDA receptor– GABA(A) receptor– L‐type Ca(2+) channels

• Ibid, Zheng.31


• Consequently, sex hormones with their neuroactivity are important regulators of synaptic transmission in the CNS including brain function.– Ibid, Zheng.

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Estrogen and Memory

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Estrogen and Memory

• Estrogen’s affects within the CNS and more specifically the hippocampus are governed by estrogen receptors alpha and beta. – Vasudevan, N., et al., “Membrane‐initiated actions of estrogens in neuroendocrinology: emerging principles,” Endocr Rev 2007; 28:1‐19.

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Reference

– Levin, E., “Integration of the extranuclear and nuclear actions of estrogen,”Mol Endocrinol 2005; 19:1951‐59.

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Estrogen and Memory (Cont.)

• Increases blood flow• Increases glucose and oxygen to the neurons• Increases neurotransmitters• Keeps the blood‐brain barrier working• Increase sensitivity to nerve growth factor

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• Protects neurons• Decreases neuronal generation of Alzheimer’s beta amyloid peptides

• Is a natural antioxidant• Increase manual speed and dexterity• Increases availability of acetylcholine

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• Boosts by 30% NMDA receptors to maintain strength and durability of synaptic connections involved in creating long‐term memories

• Decreases distractibility• Turns on progesterone receptors

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Estrogen and Memory

• Women who have had unilateral or bilateral oophorectomies before menopause have an increased risk of memory loss.– Rocca, W., et al., “Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause,”Neurology 2007; 69(11):1074‐83.

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Cognitive Symptoms Due To Menopause

• “I’m losing it.”• “I’m going crazy.”• “I’m flipping out.”• “I do the weirdest things.”• “I’m having a nervous breakdown.”• “I think I am getting early Alzheimer’s.”• “I cannot spell anymore.”

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Symptoms

• Can be four to fifteen years before menopause.

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Great Book For Your Patients

– Warga, Claire, Menopause And The Mind. New York, New York: The Free Press, 1999.

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Warga’s Hormonal Misconnection Syndrome

• The following is a list of symptoms that is referred to as Warga’s Hormonal Misconnect Syndrome. These are the symptoms that you will commonly see in your patients with memory “changes.”

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Thinking Changes

• Losing your train of thought more often • Forgetting what you came into a room to get • Not being able to concentrate as well upon demand• Feeling foggy, hazy, and cotton‐headed and not being able to clear it up at will

• Experiencing a though blockade: an inability to pull ideas out at will

• Fluctuating agility in prioritizing 44

Speech Changes

• Naming difficulties for long‐known names: children, best friends, things, places

• Finding yourself at a loss for words in how to express something while speaking

• Experiencing “It’s on the tip of my tongue but I can’t get it out” sensation

• Making malapropisms: saying wrong words that are related somehow to the intended one

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Speech Changes (Cont.)

• Reversing whole words while speaking• Reversing the first letters of words while speaking• Experiencing “echo” words as unintentional intrusions into present speech

• Relying on “filler” words more often”“whatchamacallit,” “that thing,” “you know what I mean”

• Organizing sentences and ideas less efficiently while speaking

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Changes In The “Beam” Of Attention

• Blinking social attention when interested and interacting: listening but not always attending

• Blanking‐out amnesia for what you just did• Experiencing increased distractability

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Memory Changes: Short And Long Term

• Forgetting what you just did, or past occurrences, with no threads of association to getting back to what’s missing: missing links

• Changing certainty in how words should be spelled in once good or great spellers

• Fluctuating agility in calculating and in “counting with a quick scanning look”

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Memory Changes: Short And Long Term (Cont.)

• Experiencing changes in the speed and accuracy of memory retrieval

• Forgetting the content of a movie right after seeing it but remembering your emotional reaction to it

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Behavioral Changes

• Making behavioral “malapropisms”: unintended slips in behavior that are related to the intended behavior somehow, such as putting shampoo in the refrigerator

• Forgetting briefly how to do things long known, such as where to turn on the computer

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Behavioral Changes (Cont.)

• Feeling that automatic skills such as driving for a few moments are not “automatic” in the same way as usual

• Dropping things more often that require fine finger/hand coordination

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Behavioral Changes (Cont.)

• Absentmindedly, leaving out or reversing letters in words while writing

• Forgetting how to write an word in the middle of writing and having to leave blanks

• Experiencing “translating” hesitations in converting what’s heard into writing

• Not handling the same amount of stress in the same way

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Spatial Skills Changes

• Changing skill in remembering and/or recognizing faces (not well‐known faces)

• “Looking at but not seeing” what you are looking for when it’s right there ultimately, more than in the past

• Changing reading skill in visually “seeing” and comprehending reading material

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Spatial Skills Changes (Cont.)

• Spending less time reading, without difficulties above (for formerly heavy‐duty readers)

• Forgetting briefly how to get to long‐known landmarks in your life

• Experiencing familiar locales in one’s experience as momentarily unfamiliar

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Altered Sense Of Time

• Forgetting appointments more or not anticipating events of personal importance with the same accuracy

• Forgetting important events in your personal history timeline, i.e., which breast you had biopsied

• “Living more in the moment” out of necessity: a “spliced‐film‐frames” sense of personal time

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Hormonal Misconnection Syndrome

• Cognitive/behavioral/speech episodes that are mis‐hits

• The mind’s intentions are not producing the right physiological connections that they used to in the preexisting circuitry and/or chemical flow patterns of the brain.

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Reason For Misconnections?

• A body/brain retooling or “retuning” brought on by the effects of declining ovarian function and declining estrogen hormone supplies on a thinking, remembering, attention‐creating brain that depends heavily on estrogen as a brain “transmission fluid”, as a fortifying performance‐enhancing steroid or multivitamin.

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THE WHM Syndrome Parallels Hypothyroidism

• Estrogen, progesterone, testosterone, DHEA, and cortisol changes may all trigger changes in thyroid function.

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Women And Cognitive Symptoms

• Women may be embarrassed to discuss these symptoms with their doctors.

• If you do not take a good history, you will not uncover the symptoms.

• Women may feel they will be “written off” by their doctors as incompetent or crazy.

• Symptoms may be treated with anti‐depressant, as ADD, anti‐anxiety medications, or told it is probably nothing. None of these treat the cause of the problem.

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Are These Symptoms A Normal Part Of Aging?

• Women often assume that cognitive changes are a normal part of aging and that they have to live with them, and that they are not reversible.

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Studies In Our Practice

• Show that cognitive changes at peri‐menopause and menopause are the most common symptoms of all menopause symptoms: 99.7% of women.

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Estrogen And The Brain

• “There is not a cell in the brain that is not directly or indirectly sensitive to estrogen.”– Frederick Naftolin, M.D., Professor and Chairman of Yale Medical School’s Department of Obstetrics and Gynecology

– Is also a neuroscientist

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Estrogen And The Brain• “Menopause is a state of estrogen deficiency. It is an endocrinopathy in the same way that diabetes and hypothyroidism are hormone deficiency states. People worry about bone density and coronary artery disease in the postmenopausal state, but they should also be worrying about what’s happening to the brain’s neurons.”– Dr. Dominique Toran‐Allerand. She is a neurobiologist who has been studying the role of estrogen on fetal and postnatal rat‐brain tissue for over 30 years at Columbia University’s College of Physicians and Surgeons.

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Estrogen And the Brain• Article proposed that the loss of estrogen’s important functions might “lead to age‐related impairment of memory and cognition.” He goes on to say, “such multiple roles for estrogen would suggest that reproductive senescence (ie., perimenopause and menoapuse) may have a multifaceted impact on memory loss and cognitive decline through decreased regulation of intact (memory) circuits as well as decreased protection of such circuits from degeneration.”– Morrison, J., et al., “Life and death of neurons in the aging brain,” Science,

1997; 278:412‐19.

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• Estrogen has effects on the nerve communication systems that project messages throughout the cortex and other major areas of the brain, especially the hippocampus. – McEwen, B., et al., “Observations in a preliminary open trial of estradiol therapy for senile dementia—Alzheimer’s type, “ Psychneuroendocrinol, 1986; 11(3):337‐45.

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• Estrogen affects many systems of the brain– Increases the availability of serotonin– Increases availability of acetylcholine– Increases availability of noradrenaline– Enhances transmission of dopamine

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Summary By Warga Of Research On Estrogen

• Estrogen has many affects on the brain.

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Estrogen Alters The Neurochemistry of the Brain

• By affecting the supplies of multiple neurotransmitters: serotonin, dopamine, acetylcholine, glutamate, GABA, noradrenaline

• By affecting critical enzymes (choline acetyltransferase)

• By stimulating nerve growth factors• By affecting neuropeptides• By reducing the formation of toxic brain‐destroying proteins implicated in Alzheimer’s

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Estrogen Alters The Neurochemistry Of The Brain

• By promoting uptake of the brain’s fuel‐‐glucose

• Estrogen increases choline acetyltransferase production which leads to an increase in synthesis of acetylcholine.– Luine, V., et al., “Estrogen increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats,” Experimental Neurology 1985; 80:484‐90.

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• Estrogen stimulates neuronal nitric oxide (NO) synthase which produces the neuromodulator/neurotransmitter NO.– Monacada, S., et al., “The L‐arginine nitric oxide pathway,” NEJM 1993; 329:2002‐12.

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• Estrogen stimulates the changes in the catabolism of serotonin by increasing the degradation of monoamine oxidase.– Luine, V., et al., “Effect of estradiol on turnover of type A monoamine oxidase in brain,” Jour of Neurochemistry 1977; 28:1221‐27.

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• All of the above functions are related to memory, learning, and mood.

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Estrogen Alters The Architecture And Structure Of The Brain

• By increasing the surface area of potential “docking sites” for connections to incoming messages on nerve cells arms via monthly sprouting of new spines and potential synapses

• By stimulating the growth of more dense branches on nerve cells (arborization) that potentially increase connectivity and complexity 73

Estrogen Maintains The Interconnections Of The Brain And Supports Nerve Growth

• By maintaining a denser mesh of nerve fiber outgrowths for potential connections than when it is not there

• By increasing synapse formation after neuronal damage

• By inducing nerve growth via induced release of different nerve growth factors in a complex feedback loop

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Estrogen Affects The Work Tone Of The Brain

• By stimulating and promoting the function of the brain’s cholinergic projecting system

• The serotonergic projecting system• The dopaminergic projecting system• The adrenergic projecting system• The neurotransmitter projecting system that depends on the neurotransmitter GABA

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Estrogen Increases The Neuronal Plasticity Of The Brain

• By regulating the formation and breakdown of synapses and branches

• By facilitating response to injury after strokes• By having the ability to orchestrate the turning on of different genes

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Estrogen and Memory

• Estrogen has been shown to increase the number and length of dendritic spines and the density of NMDA receptors in the hippocampus. – Ibid., Polcz.

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• During the menstrual cycle the changing levels of estrogen drive synaptic remodeling in the arcuate nucleus of the hypothalamus.

• The glia responds to estrogen by increasing its processes and increasing neuronal ensheathment.

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References

– Ibid., Polcz.– Garcia‐Segura, L., et al., “Synaptic remodeling in arcuate nucleus after injection of estradiol valerate in adult female rats,” Brain Res 1986; 366:131‐35.

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Estrogen Is Neuroprotector

• By acting as a natural antioxidant • By boosting the body’s own natural antioxidant system

• By protecting brain cells from beta‐amyloid plaque deposits

• By helping brain cells survive deprivation of vital classes of substances longer

• By increasing the expression of more nerve growth factor receptors

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Estrogen Is A Neuroprotector (Cont.)

• By recruiting the aid of nerve growth factors• By decreasing the toxicity excitotoxins such as glutamate

• By acting as an anti‐inflammatory

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References

– Toran‐Allerand, C., et al., “Estrogen receptors colocalize with low affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain,” Proceedings of the National Academy of Science 1992; 89:4668‐72.

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Estrogen Boosts The Metabolic Function Of The Brain

• By increasing availability of glucose to the brain

• By increasing cerebral blood flow and preventing ischemia

• By maintaining the elasticity of blood vessels • By increasing the resting rate of metabolism of the body

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Estrogen Acts As An Activator And Performance Enhancer

• By increasing speed of rapid limb‐coordinated movements in animals

• By increasing finger‐tapping skills and manual speed and dexterity in women

• By increasing verbal fluency, speech articulation agility, syllable repetition, speeded counting, word reading

• By increasing sensory perception: hearing, smell, visual signal detection, fine touch

• By maintaining central processing motor integration in such tasks as driving

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Estrogen As An Activator And Performance Enhancer (Cont.)

• By boosting metabolic activity of many areas of the brain and spinal cord within hours of administration

• By acting as an “upper” to increase feelings of energy and well‐being, mood, feelings of elation, and euphoria in human studies

• Boosts attention to tasks in monkeys• By decreasing distractability

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Estrogen As An Activator And Performance Enhancer (Cont.)

• By increasing reaction time in premenopausal women during estrogen‐dominant stage of cycle

• By increasing short‐term memory• By increasing performance and speed of learning in rats on sensorimotor tasks

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Estrogen Acts As A Neuromodulator

• By turning on many but not all progesterone receptors

• By boosting neurotransmitter response • By amplifying the sensitivity of a nerve cell• By strengthening the electrical pathways for memory retention for at least six to eight hours

• By making neurons more sensitive to a helpful protein substance believed to play a role in growth of dendrites and axons

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Estrogen Is A Gene Modulator

• By hooking up with estrogen receptors in the cell’s nucleus estrogen can turn on or change the expression of a host of genes inside the nucleus

• By modulating the expression of the apolipoprotein E gene estrogen may possibly affect the risk of developing Alzheimer’s disease

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Estrogen Affects Learning, Memory And Old Knowledge

• Boosts by 30 percent NMDA receptors in the hippocampus believed to be important in maintaining the strength or durability of synapse connections involved in creating longer‐term memories or learning

• By producing effects on the hippocampus (animal studies)

• By building and maintaining synapses• By maintaining verbal memory, verbal learning, and spatial memory

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Estrogen Has Cardiovascular‐Protecting Effects

• Reduced LDL and raises HDL• May slow the progression of cerebral artherosclerosis and prevent vascular dementia

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References

– Duff, S., et al., “A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy,” Horm Behav, 2000; 38(4):262‐76.

– Stevens, M., et al., “Low‐dose estradiol alters brain activity,” Psychiatry Res, 2005; 139(3):199‐217.

– Compton, J., et al., “HRT and its effect on normal ageing of the brain and dementia,” Brit Jour Clin Pharmacol, 2001; 52(6):647‐53.

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References (Cont.)

• Wise, P., et al., “Minireview: neuroprotective effects of estrogen‐new insights into mechanisms of action,” Endocrinol, 2001; 142(3):969‐73.

• Puder, J., et al., “Estrogen modulates the hypothalamic‐pituitary‐adrenal and inflammatory cytokine responses to endotoxin in women,” Jour Clin Endocrinol Metab, 2001; 86(6):2403‐8.

• Lopez‐Jaramillo, P., et al., “Improvement in functions of the central nervous system by estrogen replacement therapy might be related with an increased nitric oxide production,”Endothelium, 1999; 6(4):263‐6.

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References (Cont.)

• Bruce, A., et al., “Estrogen attenuates and corticosterone exacerbates excitotoxin oxidative injury and amyloid beta‐peptide toxicity in hippocampal neuron,” Jour of Neurochem, 1996; 66(5):1836‐44.

• Liune, V. et al., “Immuno‐chemical demonstration of increased choline acetyltranferase concentration in rat prepoptic area after estradiol administration,” Brain Res 1980; 191(1):273‐7.

• Paganini‐Hill, A., et al., “Alzheimer’s disease in women,” The Female Patient, 1998; 23:10‐20.

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References (Cont.)

• Yaffe, K., et al., “Estrogen therapy in postmenopausal women: effects on cognitive function and dementia,” JAMA, 1998; 279(9):688‐95.

• Strivastava, R., et al., “Apolipoprotein E gene expression in various tissues of mouse and regulation by estrogen,” Biochem Mol Biol Int, 1996; 38:91‐101.

• Yaffe, K., et al., “Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women,” Arch Neuro, 1998; 54:1110‐14..

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References (Cont.)

• Poehlman, E., et al., “Changes in energy balance and body composition at menopause: a controlled longitudinal study,” Ann of Int Med, 1995; 123(9):673‐75.

• Sarrel, P., et al., “Ovarian hormones: recent findings of cardiological significance,” Cardiology in Practice, 1991:Mar‐Apr, 14‐17.

• Simpkins, J., et al., “Estrogen and memory protection,” Jour Soc of Obstet & Gyn of Canada, 1997; Supplement: 14‐19.

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References (Cont.)

• Henderson, V., et al., “Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects,”Arch of Neur, 1994; 51(9):896‐900.

• Sherwin, B., et al., “Estrogen use and verbal memory in healthy post‐menopausal women,” Obstetrics & Gyn, 1994; 83(6):979‐83.

• Phillips, S., et al., “Effects of estrogen on memory function in surgically menopausal women,” Psycho Neuroendo, 1992; 17(5):485‐95.

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References (Cont.)

• Di Paolo, T., et al., “Modulation of brain dopamine transmission by sex steroids, Rev Neurosci, 1995; 5:27‐41.

• Williams, G.V., et al., “Modulation of memory fields by dopamine D1 receptors in prefrontal cortex,”nature, 1995; 376(6541):572‐75.

• Paganini‐Hill, A., et al., “Does estrogen replacement therapy protect against Alzheimer’s disease? Osteoporosis Int, 1997; Supp 1:S12‐17.

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References (Cont.)

• Shaywitz, S., et al., “Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks,” JAMA, 1999; 281(13):1197‐202.

• Drake, E., et al., “Associations between circulating sex steroid hormones and cognition in normal elderly women,” Neurology, 2000; 54(3):599‐603.

• Duka, T., et al. “The effects of 3‐week estrogen hormone replacement on cognition in elderly healthy females,” Psychopharmacol, 2000; 149(2):129‐39.

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References (Cont.)

• Paganini‐Hill, A., et al., “Estrogen replacement therapy and risk of Alzheimer’s disease,” Arch Int Med, 1996; 156(19):2213‐17.

• Henderson, V., et al., “Estrogen replacement therapy for the prevention and treatment of Alzheimer’s disease,” CNS Drugs, 1997; 5:343‐51.

• Asthana, S., et al., “Transdermal estrogen improves memory in women with Alzheimer’s disease.”(abstract), Neurosci Abstr, 1996; 22:200.

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References (Cont.)

• Henderson, V., et al., “Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease,”Psychoneuroendocrinol, 1996; 2194):421‐30.

• Simpkins, J., et al., “Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer’s disease,”Amer Jour Med, 1997; 103(3A):19S‐25S.

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Estrogenic Effects on Neurons

• Estrogen effects the alteration of potassium permeability in the postsynaptic membrane of the medial amygdala neurons and the postsynaptic potentiation of non N‐methyl‐D‐aspartate (NMDA) receptors in the C1 neurons of the hippocampus.

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Reference

– Wong, M., et al., “Long‐term and short‐term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons.,” Jour of Neuroscience 1992; 12(8):321725.

– Ibid., Polcz.

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Estrogenic Effects on Neurons

• Synaptic transmission is also modulated by estrogen effects on the Ca2+ transport mechanisms in nerve endings.– Nikezic, G., et al., “17 beta‐estradiol in vitro affects Na‐dependent and depolarization‐induced Ca2+ transport in rat brain synaptosomes,”Experimentia 1996; 52(3):217‐220.

– Ibid., Polcz.

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Estrogen and Memory

• Estrogen has been shown to increase the cerebral circulation in women after menopause which has been associated with an improvement in memory.– Gangar, K., et al., “Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause,” Lancet 1991; 338:839‐42.

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Reference

– Barrett‐Conner, E., et al., “Estrogen replacement therapy and cognitive function in older women,”JAMA 1993; 269:2637‐41.

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Major Studies On Estrogen And Memory

• Researchers in this 1996 study found a 54 percent reduction in the risk of developing Alzheimer’s disease in those who had taken estrogen. These women had been tracked for up to sixteen years.– Morrison, A., et al., “A prospective study of ERT and the risk of developing Alzheimer’s disease in the Baltimore longitudinal study of aging,”abstract, Neurol 1996:46:A435‐6.

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Major Studies (Cont.)

• In another 1996 study scientists found that estrogen reduced by 50%, not only the risk of developing Alzheimer’s disease, but delayed the onset of the disease, even in those at increased hereditary risk of developing Alzheimer’s disease. – Tang, M., et al., “Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease,” Lancet, 1996; 348(9025):429‐32.

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• A recent study conducted on 1,889 older women in Utah revealed that women who had taken ERT were 40% less likely to develop Alzheimer’s disease. Furthermore, the longer they were on hormone replacement therapy the lower was their risk.– Zandi, P., et al., “Hormone replacement therapy incidence of Alzheimer’s disease in older women,”JAMA 2002; 288 (17):2123‐29.

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• In a prospective study the rate of developing Alzheimer’s disease among patients using estrogen was less than among patients who had never used estrogen.– Paganini‐Hill, A., et al., “Estrogen deficiency and risk of Alzheimer’s disease in women,” Amer Jour of Epidemiology 1994; 140:256‐61.

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• Estradiol hormone replacement has an affect on cholinergic function which may benefit memory.

• Estrogen replacement therapy has been shown to positively influence– Attention span– Concentration

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Major Studies (Cont.)• Estrogen replacement therapy has been shown to improve cognition and regional cerebral blood flow in women with Alzheimer’s disease.

• Ohkura, T., et al., “ERT for dementia of the Alzheimer type in women,” in Berg, G., et al., (Eds.), The Modern management of the Menopause. Proceedings of the VII International Congress on the Menopause. Stockholm, Sweden. London, NY: Parthenon Publishing Group, 1993; p. 315‐33.

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• Estrogen supplementation has been shown to prevent and/or delay the onset of Alzheimer’s disease.– Ibid., Polcz.

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References

– Tang, M., et al., “Effect of estrogen during menopause on risk and age at onset of Alzheimer’s disease,” Lancet 1996; 348:429‐32.

– Paganini‐Hill, A., et al., “Estrogen deficiency and risk of Alzheimer’s disease in women,” Amer Jour of Epidemiology 1994; 140:256‐61.

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References

– LeBlanc, E., et al., “Hormone replacement therapy and cognition: systemic review and meta‐analysis,” JAMA 2001; 285:1489‐99.

– Hogervorst, E., et al., “The nature of the effect of female gonadal hormone replacement therapy on cognitive function in postmenopausal women: a meta‐analysis,” Neuroscience 2000; 101:485‐512.

114


• Estrogen replacement has been shown to improve memory in postmenopausal women without dementia.– Ibid., Polcz.

115


• Estrogen replacement therapy has been shown to be most effective to maintain cognition if taken during the onset of menopause and the first few years afterward. – Gibbs, R., et al., “Estrogen and cognition: applying preclinical findings to clinical perspectives,” Jour Neurosci Res 2003; 74(5):637‐43.

116

References

– Henderson, V., et al., “Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age,” Jour Nerol Neurosurg Psychiatr 2005; 76:103‐05.

– Zandi, P., et al., “Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study,” JAMA 2002; 288:2123‐39.

117

Estrogen: Men and Memory

• Estradiol has a protective effect on the brain structures in older males. – Gibbs, R., et al., “Estrogen and cognition: applying preclinical findings to clinical perspectives,” Jour Neurosci Res 2003; 74(5):637‐43.

118

Estrogen: Men and Memory (Cont.)

• Serum estradiol and testosterone levels have been shown to be lower in men with Alzheimer’s disease compared with age‐matched controls.– Hogervorst, E., et al., “Serum total testosterone is lower in men with Alzheimer’s disease,” Neuro Endocrinol Lett 2001; 22(3):163‐68.

119

Reference

– Bowen, R., et al., “An association of elevated serum gonadotropin concentrations and Alzheimer disease?” Jour Neuroendocrinol 2000; 12(4):351‐54.

120

Progesterone and Memory

121

Progesterone Effects on Neurons

• Progesterone stimulates the release of dopamine in striatal tissue. – Ibid., Polcz.

122

Progesterone Effects on Neurons (Cont.)

• Stimulates the release of GnRh from hypothalamic neurons after binding to specific sties on the cell membrane to affect movement and autonomic functions.– Ibid., Polcz.

123


• Progesterone modulates oxytocin receptor binding in the hypothyalmus.– Ibid., Polcz.

124


• Progesterone inhibits opioid receptor binding.– Ibid., Polcz.

125


• Progesterone effects the potentiation of GABA.– Ibid., Polcz.

126


• Progesterone directs the incorporation of steroids into the cell membrane.– Ibid., Polcz.

127

Progesterone and Memory

• Progesterone is made in the brain, spinal cord, and peripheral nerves from pregnenolone.

• Progesterone may promote the formation of myelin sheaths.

• Scientists are now looking at progesterone replacement to aid in the prevention of memory loss.

128

Reference

– Schumacher, M., et al., “Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination,” Growth Horm IGF Res 2004; Jun, (Suppl):S18‐S33.

129

Neuroprotective Effects of Progesterone

• Study looked at progesterone and allopregnanolone treatment in patients after global cerebral ischemia.

• Progesterone and allopregnanolone reduced the impairment in spatial learning and memory, as well as in reference and working memory, and prevented the narrowing of the hippocampus which is otherwise induced by ischemia.

130

Reference

– Morali, G., et al., “Neuroprotective effects of progesterone and allopregnanolone on long‐term cognitive outcome after global cerebral ischemia,”Restor Neurol Neurosci 2011; 29(1):1‐15.

131

Testosterone and Memory

132

Testosterone and Memory

• Testosterone helps to both men and women with cognitive function.

133

Women: Testosterone and Memory

• A small pilot study that was just completed suggests that testosterone replacement might protect the memory of healthy aging women.

• Transdermal testosterone spray was used in this trial.– Davison, S., Endocrine Society 93rd annual meeting 2011, Abstract P1‐314.

134

Women: Testosterone and Memory (Cont.)

• The hormonal symphony is very important with relationship to hormonal function and cognition.

• Without enough estrogen, testosterone cannot attach to the brain receptors.

135

Men: Testosterone and Memory

• In men, testosterone levels decline at a rate of approximately 1% per year starting at the age of 30. – Morley, J., et al., “Longitudinal changes in testosterone, luteinizing hormone, and follicle‐stimulating hormone in healthy older men,”Metabolism 1997; 46:410‐13.

136

Men: Testosterone and Memory (Cont.)

• Testosterone levels that are bioavailable decline at twice the rate of total testosterone levels.– Morley, J., et al., “Evaluation of assays available to measure free testosterone,”Metabolism 2002; 51:554‐59.

137


• 30% to 60% of men in their 70s are hypogonadal. – Wang, C., et al., “ISAm ISSAm, EAU, EAA, and ASA recommendations: investigation, treatment and monitoring of late‐onset hypogonadism in males,”Aging Male 2009; 12:5‐12.

138


• Men develop Alzheimer’s disease at a rate that is slower than women.

• Men with dementia have a higher mortality rate. – Lee, M., et al., “Dementia and life expectancy: what do we know?” Jour Amer Med Dir Assoc 2009; 10:466‐71.

139


• The development of memory loss in males is related to the loss of testosterone that occurs with age in a male. – Flood, J., et al., “Age‐related decrease of plasma testosterone in SAMPS mice: replacement improves age‐related impairment of learning and memory,” Physiol Behav 1995; 57:669‐73.

140


• In men, testosterone plays a major role in brain functioning.

• Subclinical androgen deficiency has been suggested to increase the expression of amyloid‐B‐related peptides in vivo.

141

Reference

– Gillett, M., et al., “Relationship between testosterone sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia,” Jour Alzheimer’s Dis 2003; 5:267‐69.

142


• In this study, age‐related decline in free testosterone predicted age‐related decline in visual and verbal memory.– Morley, J., et al., “Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dihydroepiandrosterone sulfate, and the ratio of insulin‐like growth factor 1 to growth hormone,” Proc Natl Acad Sci USA 1997; 94:7537‐42.


• Low levels of bioavailable testosterone are a positive predictor of memory loss in men as they age.– Morley, J., et al., “Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin‐like growth factor 1 to growth hormone,” Proc Natl Acad Sci USA 1997; 94:7537‐42.

144


• In a medical trial done in Hong Kong, in men with low bioavailable testosterone levels there was a strong correlation with memory loss/Alzheimer’s disease.– Chu, L., et al., “Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men,” Clin Endocrinol 2008; 68:589‐98.

145


• Males that have a higher ratio of total testosterone to SHBG have a lower rate of development of Alzheimer’s disease. – Moffat, S., et al., “Free testosterone and risk for Alzheimer disease in older men,” Neurology 2004; 62:188‐93.

146


• Patients with Alzheimer’s disease have been shown to have a lower ratio of total testosterone to SHBG when compared with age‐matched controls.– Hogervorst, E., et al., “Low free testosterone is an independent risk factor for Alzheimer’s disease,”Exp Gerontol 2004; 39:1633‐39.

147


• In another medical trial, which was a prospective longitudinal study, revealed that the risk of Alzheimer’s disease was decreased by 26% for each 10‐unit (nmoL/nmoL) increase in free testosterone at 2, 5, and 10 years before the diagnosis of Alzheimer’s disease was made.

148

Reference

– Moffat, S., “Effects of testosterone on cognitive and brain aging in elderly men,” Ann NY Acad Sci 2005; 1055:80‐92.

149


• Low levels of testosterone may occur prior to the diagnosis of Alzheimer’s disease.– Ibid., Moffat.

150


• Low testosterone levels have also been associated with mild memory loss.– Chu, L., et al., “Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men,” Clin Endocrinol (Oxf) 2008; 68(4):589‐98.

151


• Studies have also shown a correlation between testosterone levels and cognitive abilities such as spatial performance and mathematical reasoning. – McKeever, W., et al., “Testosterone, dihydrotestosterone and spatial task performance of males,” Bull Psychon Soc 1990; 28:305‐08.

152


• Studies done in animals have shown that depletion of androgens results in increased pathologic conditions that are associated with Alzheimer’s disease.– Increased antibody levels– Increased neuronal death– Hyperphosphorylation

153

Reference

– Drummond, E., et al., “Androgens and Alzheimer’s disease,” Curr Opin Endocrinol Diabetes Obes 2009; 16:254‐59.

154


• Studies in animals also have shown that both testosterone and dihydrotestosterone have an effect on the upregulation of the hippocampal neurogenesis in adult male rats.

155

Reference

– Galea, l., et al., “Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behavior,” Can Jour Exp Psychol 2008; 62:247‐60.

156


• Higher levels of free concentrations have been associated with better performance in specific aspects of memory and cognitive function.

• Optimal processing capacity was found in men between the ages of 35 and 90 even after adjustment for age, education, and CV morbidity.

157

References

– Yaffe, K., et al., “Sex hormones and cognitive function in older men,” Jour Amer Geriatr Soc 2002; 50:707‐12.

– Thilers, P., et al., “The association between endogenous free testosterone and cognitive performance: a population based study in 35 to 90 year‐old men and women,”Psychoneuroendocrinology 2006; 31:565‐76.

158


• The same was not true of total testosterone levels.– Yeap, B., et al., “Higher serum free testosterone is associated with better cognitive function in older men, whilst total testosterone is not. The Health In Men Study,” Clin Endocrinol 2008; 68:404‐12.

159


• In men that have undergone hormonal treatments for prostate cancer with suppression of endogenous testosterone synthesis and blockade of the androgen receptor, studies have shown that there is a beneficial effect on verbal memory but an adverse effect on spatial performance.

160

Reference

– Cherrier, M., et al., “The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer,”Jour Urol 2003; 170:1808‐11.

161


• These same patients also had visuomotor slowing and slowed reaction times in several attentional domains. – Salminen, E., et al., “Associations between serum testosterone fall and cognitive function in prostate cancer patients,” Clin Cancer Res 2004; 10:7575‐82.

162


• In the same patients plasma amyloid levels elevated as testosterone levels declined. – Ibid., Salminen.

163


• When treatment was discontinued, memory improved but visuospatial abiltities did not. – Almeida, O., et al., “One year follow‐up study of the association between chemical castration, sex hormones beta‐amyloid, memory and depression in men,” Psychoneuroendocrinology 2004; 29(8):1071‐81.

164


• Study showed that testosterone therapy in elderly men showed some reversal of cognitive dysfunction. – Lyngdorf, P., et al., “Epidemiology of erectile dysfunction and its risk factors: a practice‐based study in Denmark,” Int Jour Impot Res 2004; 16:105‐11.

165


• Testosterone therapy has been shown to help with mild cognitive impairment. – Morley, J., “Testosterone and behavior,” Clin Geriatr Med 2003; 19:605‐16.

166


• Testosterone replacement helps to prevent the production of beta amyloid precursor protein in men.– Gouras, G., et al., “Testosterone reduces neuronal secretion of Alzheimer’s beta‐amyloid peptides,”Proc Nat Acad Sci USA 2000; 97(3):1202‐05.

167


• Animal studies have shown that testosterone replacement can improve memory possibly by reducing amyloid‐B peptide production.– Flood, J., et al., “Age‐related decrease of plasma testosterone in SAMP8 mice: replacement improves age‐related impairment of learning and memory,’ Physiol Behav 1995; 57:669‐73.

168


• Testosterone therapy in older hypogonadal men improved spatial cognition and verbal fluency.– Orwoll, E., et al., “Transdermal testosterone supplementation in normal older men. Proceedings of the 74th meeting of The Endocrine Society, San Antonio, TX, 1992; p. 319.

169

Reference

– Alexander, G., et al., “Androgen‐behavior correlations in hypogonadal men and eugonadal men,” Horm Behav 1998; 33:85‐94.

170


• In older men without dementia testosterone replacement reduced working memory errors. – Janowsky, J., et al., “Sex steroids modify working memory,” Jour Cogn Neurosci 2000; 12:407‐14.

171


• Testosterone replacement in men in this study improved verbal and spatial memory. – Cherrier, N., et al., “Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report,” Jour Androl 2003; 24:568‐76.

172


• In this trial testosterone improved verbal and spatial memory and constructional abilities in nonhypogonadal men with mild memory loss and early Alzheimer’s disease.– Cherrier, M., et al., “Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment,” Neurology 2005; 64:2063‐68.

173

Men and Dementia• One form of dementia that men may have is Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS). – Leehey, M., et al., “Fragile X‐associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment,” Jour Investig Med 2009; 5:830‐36.

• Average age of onset is 60.• Verbal understanding is preserved. 174

Men and Dementia

• Symptoms of FXTAS– Impaired balance tremor– Parkinsonism symptoms– Decline in executive function– Decline in processing speed– May have irritability, hostility, and agitation

• Little, M., et al., “Aging male,” in Morley, J., (Ed.). The Aging Male. Clinics in Geriatric Med 2010; 26(2):171‐84.

175

Men and Dementia (Cont.)

• MRI done on patients with FXTAS shows increased T2 signaling in the middle cerebellar pedundes.

• Dx: confirming the existence of high level of CGG repeats in the fragile X mental retardation1 gene.– Ibid., Little.

176

DHEA and Memory

177

DHEA and Memory

• Low DHEA levels due to stress and aging lead to cognitive decline.

• Patients with Alzheimer’s disease have levels of DHEA that are 48% lower than their normal counterparts.

178

DHEA and Memory (Cont.)

• Studies are mixed as to whether DHEA replacement has a strong effect on memory.– Farr, S., et al., “DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice,” Life Sci 2004; 75:2775‐85.

– Grimley, E., et al., “Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people,” Cochrane Database Syst Rev 2006; 4:CD006221.

179

References

– Haren, M., et al., “Lower serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle‐aged to older African American women,”Maturitas 2007; 57:347‐60.

– Morley, J., “Hormones and the aging process,”Jour Amer Geriatr Soc 2003; 51(Suppl 7):S333‐S337.

180

DHEA and Memory

• In studies on DHEA in the military, warfighters who exhibited higher levels of DHEA during extreme stress were those who also had better hippocampal and prefrontal dependent cognitive abilities during stress.

181

References

• Morgan, C., et al., “Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels , symptoms of dissociation and objective performance in humans exposed to acute stress,” Arch of Gen Psychiatry 2004; 61(8):819‐25.

• Morgan, C., et al., “Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation and objective performance in humans exposed to underwater navigation stress,” Biological Psychiatry 2009; 66(4):334‐40.

182

DHEA and Memory

• Recent double‐blind, placebo‐controlled, crossover study in which DHEA was given to postmenopausal women.

• Study showed a large benefit of DHEA replacement therapy on mental rotation, subject‐ordered pointing, fragmented picture identification, perceptual identification, and same‐different judgment.

183

Reference

– Stangl, B., et al., “Administration of dehydroepiandrosterone (DHEA) enhances visual‐spatial performance in postmenopausal women,”Behav Neuroci 2011; 125(5):742‐52.

184

Treatment

• Optimization of hormonal function in both me women and men.

• Case histories

185

186

Summary

• Stacking triad 5 with triad 2• The sex hormones affect cognitive function and memory.

• All of them have to be working in concert in order for the patient to have optimal health.

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