9/26/2016 Hormone Therapy and Cognition in the Menopause - PDF document

9/26/2016 Hormone Therapy and Cognition in the Menopause DISCLOSURES Transition: Critical Questions Remain Unanswered • No conflicts of interests Pauline M. Maki, PhD Professor of Psychiatry and Psychology University of Illinois at Chicago 3 rd Utian Translational Science Symposium Early use of HT has neutral effect on cognitive function First – Acknowledge Progress!!! WHIMSY (WHI Memory Study of Younger Women) 1 • WHIMS-Y • CEE alone or with MPA in women (50 to 54 y) upon enrollment; n =1326 • KEEPS • 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 • ELITE 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. 1

9/26/2016 KEY GAPS IN KNOWLEDGE KEY GAPS IN KNOWLEDGE 1. Does HT affect cognition in women for whom HT is indicated 1. Does HT affect cognition in women for whom HT is indicated – i.e., women with moderate to severe VMS? – i.e., women with moderate to severe VMS? 2. Does use of HT or oral contraceptives in the perimenopause 2. Does use of HT or oral contraceptives in the perimenopause – as distinct from the early postmenopause - enhance – as distinct from the early postmenopause - enhance cognition? cognition? 3. Does early use of HT have effects on Alzheimer’s disease 3. Does early use of HT have effects on Alzheimer’s disease risk and the neuropathology underlying risk? risk and the neuropathology underlying risk? 4. Is HT effective in preventing cognitive decline in women who 4. Is HT effective in preventing cognitive decline in women who undergo early surgical menopause? undergo early surgical menopause? Measuring Physiologic VMS Objectively with Ambulatory Objective VMS are associated with worse verbal Monitors memory • Biolog Skin Conductance (score adjusted for other significant predictors) (score adjusted for other significant predictors) 6 6 Monitor 5 5 29 midlife women (mean 4 4 age = 53 y) with • Objective hot flash defined as Delayed Paragraph Recall Delayed Paragraph Recall 3 3 moderate to severe hot flashes 2 2 a 2 mmho increase in skin 1 1 conductance across a 30 Number of hours of 0 0 sleep independently -1 -1 second period predicted worse memory -2 -2 -3 -3 • Button press used for -4 -4 subjective recognition of hot -5 -5 -6 -6 flash -6 -6 -5 -5 -4 -4 -3 -3 -2 -2 -1 -1 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Total Number of Objective Hot Flashes during Sleeping Hours Total Number of Objective Hot Flashes during Sleeping Hours 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. 2

9/26/2016 Decreases in physiologic VMS relate to improvements in verbal Physiologic VMS are associated with adverse brain memory in a clinical trial of stellate ganglion blockade outcomes Moderate to severe VMS r=0.51, p<0.05 More white matter hyperintensities Hyperconnectivity in brain at rest, especially in hippocampus 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. 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. 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. Thurston RC, Maki PM, Derby CA, Sejdi ć 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 Memory performance is unrelated to reported vasomotor symptoms hippocampus & prefrontal cortex during memory task • 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. Maki, P et al. (in preparation); n=13; mean age 54.7; 3

9/26/2016 Memory Performance Worsens during the Perimenopause even after KEY GAPS IN KNOWLEDGE Controlling for Age Penn Ovarian Aging Study 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? 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. PRELIMINARY DATA SUGGEST THAT ORAL ENDOCRINE CHANGES AROUND THE FMP CONTRACEPTIVES ENHANCE VERBAL MEMORY 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 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. 4

9/26/2016 SUPPORT FOR THE CRITICAL WINDOW HYPOTHESIS KEY GAPS IN KNOWLEDGE FOR AD 1. Does HT affect cognition in women for whom HT is indicated • Three prospective studies have examined timing of – i.e., women with moderate to severe VMS? initiation of HT in relation to risk of AD 2. Does use of HT or oral contraceptives in the perimenopause • Each of the three provides support for the timing – as distinct from the early postmenopause - enhance hypothesis cognition? • Unfortunately, a randomized clinical trial to test that 3. Does early use of HT have effects on Alzheimer’s disease hypothesis is not feasible risk and the neuropathology underlying risk? 4. Is HT effective in preventing cognitive decline in women who 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. undergo early surgical menopause? 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. KEY GAPS IN KNOWLEDGE NEUROIMAGING IN KEEPS 1. Does HT affect cognition in women for whom HT is indicated BETA-AMYLOID DEPOSITION VENTRICLE VOLUME – 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 Month undergo early surgical menopause? Kantarci K et al. Early Postmenopausal Transdermal 17 β -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. 5