[PDF] - 9/26/2016 Hormone Therapy and Cognition in the Menopause PDF Document

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Hormone Therapy and Cognition in the Menopause Transition: Critical Questions Remain Unanswered

Pauline M. Maki, PhD Professor of Psychiatry and Psychology University of Illinois at Chicago

3rd Utian Translational Science Symposium

DISCLOSURES

No conflicts of interests

First – Acknowledge Progress!!!

WHIMS-Y
KEEPS
ELITE

Early use of HT has neutral effect on cognitive function

WHIMSY (WHI Memory Study of Younger Women)1

CEE alone or with MPA in women (50 to 54 y) upon enrollment; n =1326
Published: neutral cognitive effects when tested on average 7.2 years after the trials ended
“CEE-based therapies produced no overall sustained benefit or risk to cognitive function

when administered to postmenopausal women aged 50–55 years” Keeps (Kronos Early Estrogen Prevention Study)2

5-yr cyclic transdermal E2 (50 g/wk) or CEE (0.45 mg) plus micro P (200 mg,12 d/month) in 693

women (42-58 yrs) < 36 m of FMP

Neutral cognitive effects after 48 m; some mood benefit with CEE on depression and anxiety

ELITE (Early Versus Late Intervention Trial with Estradiol)3

Oral E2 1 mg/d + vaginal P gel for 10 days per month in 567 younger (< 6 y since FMP) and older (>

10 y since FMP)

Neutral effects

1Espeland et al. 2014, JAMA Intern Med. 2Gleason et al. 2015, Plos Med. 3Henderson et al. 2016, Neurology.

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KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who

undergo early surgical menopause?

KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who

undergo early surgical menopause?

Biolog Skin Conductance

Monitor

Objective hot flash defined as

a 2 mmho increase in skin conductance across a 30 second period

Button press used for

subjective recognition of hot flash

Measuring Physiologic VMS Objectively with Ambulatory Monitors Objective VMS are associated with worse verbal memory

6 5 4 3 2 1

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Total Number of Objective Hot Flashes during Sleeping Hours 6 5 4 3 2 1

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Delayed Paragraph Recall (score adjusted for other significant predictors)

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Total Number of Objective Hot Flashes during Sleeping Hours 6 5 4 3 2 1

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Delayed Paragraph Recall (score adjusted for other significant predictors)

29 midlife women (mean age = 53 y) with moderate to severe hot flashes Number of hours of sleep independently predicted worse memory

Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause. 2008;15(5):848- 856.

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Decreases in physiologic VMS relate to improvements in verbal memory in a clinical trial of stellate ganglion blockade

r=0.51, p<0.05

Walega DR, Rubin LH, Banuvar S, Shulman LP, Maki PM. Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal

women. Menopause. Aug 2014;21(8):807-814.

Maki PM, Rubin LH, Savarese A, Drogos L, Shulman LP, Banuvar S, Walega DR. Stellate ganglion blockade and verbal memory in midlife women: Evidence from a randomized trial.

Maturitas. 2016 Oct 31;92:123-9.

Moderate to severe VMS

Physiologic VMS are associated with adverse brain

utcomes

Thurston RC, Aizenstein HJ, Derby CA, Sejdic E, Maki PM. Menopausal hot flashes and white matter hyperintensities. Menopause. 2016 Jan 1;23(1):27-32.

More white matter hyperintensities Hyperconnectivity in brain at rest, especially in hippocampus

Thurston RC, Maki PM, Derby CA, Sejdić E, Aizenstein HJ. Menopausal hot flashes and the default mode network. Fertility and sterility. 2015 Jun 30;103(6):1572-8.

Higher number of objective VMS linked to greater activation in hippocampus & prefrontal cortex during memory task

Maki, P et al. (in preparation); n=13; mean age 54.7;

Memory performance is unrelated to reported vasomotor symptoms

Ford N, Slade P, Butler G. An absence of evidence linking perceived memory

problems to the menopause. Br J Gen Pract. 2004;54(503):434-8.

Polo-Kantola P, Erkkola R. Sleep and the menopause. J Br Menopause Soc.

2004;10(4):145-50.

LeBlanc ES, Neiss MB, Carello PE, Samuels MH, Janowsky JS. Hot flashes

and estrogen therapy do not influence cognition in early menopausal women.

Menopause. 2007;14(2):191-202.
Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively

related to verbal memory performance in midlife women. Menopause. 2008;15(5):848-856.

Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms

and cognitive performance: results from the Study of Women's Health Across the Nation. Am J Epidemiol. 2010;171(11):1214-1224.

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KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who

undergo early surgical menopause? Memory Performance Worsens during the Perimenopause even after Controlling for Age

n = 403 followed for 14 years Epperson CN, Sammel MD, Freeman EW. Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab. Sep 2013;98(9):3829-3838.

Penn Ovarian Aging Study

ENDOCRINE CHANGES AROUND THE FMP

n = 1216 Randolph et al. Change in Follicle-Stimulating Hormone and Estradiol Across the Menopausal Transition: Effect of Age at the Final Menstrual Period J Clin Endocrinol Metab, March 2011, 96(3):746–754

PRELIMINARY DATA SUGGEST THAT ORAL CONTRACEPTIVES ENHANCE VERBAL MEMORY

Mordecai KL, Rubin LH, Maki PM. Effects of menstrual cycle phase and oral contraceptive use on verbal memory. Hormones and Behavior. 2008 Jul 31;54(2):286-93.

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KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who

undergo early surgical menopause?

SUPPORT FOR THE CRITICAL WINDOW HYPOTHESIS FOR AD

Three prospective studies have examined timing of

initiation of HT in relation to risk of AD

Each of the three provides support for the timing

hypothesis

Unfortunately, a randomized clinical trial to test that

hypothesis is not feasible

Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA. Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age. J Neurol Neurosurg Psychiatry. Jan 2005;76(1):103-105. Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: New findings from the Cache County Study. Neurology. Oct 30 2012;79(18):1846-1852. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. Jan 2011;69(1):163-169.

NEUROIMAGING IN KEEPS

Kantarci K et al. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. Journal of Alzheimer's Disease. 2016 May 7(Preprint):1-0. Kantarci K et al. Effects of hormone therapy on brain structure A randomized controlled trial. Neurology. 2016 Aug 30;87(9):887-96. Month

BETA-AMYLOID DEPOSITION VENTRICLE VOLUME

KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who

undergo early surgical menopause?

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Rocca WA et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69:1074-1083. Rocca WA et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69:1074-1083. 10 20 30 40 40 50 60 70 80

Age (years) Incidence (%) Oophorectomy > 48 y Other women Oophorectomy ≤ 48 y

Mayo Clinic Cohort Study of

Oophorectomy and Aging

Use of estrogen therapy until age 50

removed that risk

REMOVAL OF OVARIES BEFORE AGE 48 INCREASES RISK OF AD BY 70% KEY GAPS IN KNOWLEDGE

1. Does HT affect cognition in women for whom HT is indicated

– i.e., women with moderate to severe VMS?

2. Does use of HT or oral contraceptives in the perimenopause

– as distinct from the early postmenopause - enhance cognition?

3. Does early use of HT have effects on Alzheimer’s disease

risk and the neuropathology underlying risk?

4. Is HT effective in preventing cognitive decline in women who