Hypothalamic–pituitary–gonadal axis regulates the reproductive system. The overall health and wellbeing of a woman is subject to fluctuations in the sex hormones throughout her lifespan. Menopause, either natural or surgically induced, is often associated with cognitive complaints, especially memory disturbances. Sex hormones, besides affecting the reproductive function, affect the central nervous system in many ways. Here, we aim to review the role of sex hormones in cognition and the current evidence on use of or against menopausal hormonal therapy as a cognition enhancer in women with cognitive disturbances, including those with Alzheimer’s disease.
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Gourie-Devi M. Epidemiology of neurological disorders in India: review of background, prevalence and incidence of epilepsy, stroke, Parkinson’s disease and tremors. Neurol India. 2014;62(6):588–98.
Banerjee TK, Dutta S, Das S, et al. Epidemiology of dementia and its burden in the city of Kolkata, India. Int J Geriatr Psychiatry. 2017;32(6):605–14.
Dubey M, Ram U, Ram F. Threshold levels of infant and under-five mortality for crossover between life expectancies at ages zero, one and five in India: a decomposition analysis. PLoS ONE. 2015;10(12):e0143764.
Alzheimer’s NM. Disease: prototype of cognitive deterioration, valuable lessons to understand human cognition. Neurol Clin. 2016;34(1):69–131.
American Psychiatric Association. DSM-5: diagnostic and statistical manual of mental disorders, vol. 5. Washington, DC: American Psychiatric Association; 2013.
Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci. 2016;18(4):437–46.
GBD. Dementia collaborators global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2016;18(1):88–106.
Hersi M, Irvine B, Gupta P, et al. Risk factors associated with the onset and progression of Alzheimer’s disease: a systematic review of the evidence. Neurotoxicology. 2017;2017(61):143–87.
Hickman RA, Faustin A, Alzheimer WT. disease and its growing epidemic: risk factors, biomarkers, and the urgent need for therapeutics. Neurol Clin. 2016;34(4):941–53.
Gliebus GP. Memory dysfunction continuum (MinneapMinn). Behav Neurol Psychiatry. 2018;24(3):727–44.
Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7(3):137–52.
Bhattacharyya KB. James wenceslaus papez, his circuit, and emotion. Ann Indian Acad Neurol. 2017;20(3):207–10.
Hamson DK, Roes MM, Galea LA. Sex hormones and cognition: neuroendocrine influences on memory and learning. Compr Physiol. 2016;6(3):1295–337.
Palm R, Ayala-Fontanez N, Garcia Y, et al. Neuroendocrinology-based therapy for Alzheimer’s disease. BioFactors. 2012;38(2):123–32.
Vadakkadath Meethal S, Atwood CS. The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain. Cell Mol Life Sci. 2005;62(3):257–70.
Gurvich C, Hoy K, Thomas N, et al. Sex differences and the influence of sex hormones on cognition through adulthood and the aging process. Brain Sci. 2018;8(9):E163.
Vogel JJ, Bowers CA, Vogel DS. Cerebral lateralization of spatial abilities: a meta-analysis. Brain Cogn. 2003;52(2):197–204.
Yaffe K, Lui LY, Zmuda J, et al. Sex hormones and cognitive function in older men. J Am Geriatr Soc. 2002;50(4):707–12.
LeBlanc ES, Wang PY, Janowsky JS, et al. Osteoporotic fractures in men (MrOS) research group. Association between sex steroids and cognition in elderly men. Clin Endocrinol (Oxf). 2010;72(3):393–403.
Roldán-Tapia MD, Cánovas R, León I, et al. Cognitive vulnerability in aging may be modulated by education and reserve in healthy people. Front Aging Neurosci. 2017;9:340.
Mitchell ES, Woods NF. Cognitive symptoms during the menopausal transition and early postmenopause. Climacteric. 2011;14(2):252–61.
Weber MT, Rubin LH, Maki PM. Cognition in perimenopause: the effect of transition stage. Menopause. 2013;20(5):511–7.
Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017;317(7):717–27.
Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: a systematic review and meta-analysis. J Steroid Biochem Mol Biol. 2014;2014(142):90–8.
Epperson CN, Sammel MD, Freeman EW. Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab. 2013;98:3829–38.
Luine VN. Estradiol and cognitive function: past, present and future. Horm Behav. 2014;66(4):602–18.
Hara Y, Waters EM, McEwen BS, et al. Estrogen effects on cognitive and synaptic health over the life course. Physiol Rev. 2015;95(3):785–807.
Frankfurt M, Gould E, Woolley CS, et al. Gonadal steroids modify dendritic spine density in ventromedial hypothalamic neurons: a Golgi study in the adult rat. Neuroendocrinology. 1990;51(5):530–5.
Tuscher JJ, Luine V, Frankfurt M, et al. Estradiol-mediated spine changes in the dorsal hippocampus and medial prefrontal cortex of ovariectomized female mice depend on ERK and mTOR activation in the dorsal hippocampus. J Neurosci. 2016;36(5):1483–9.
Luine V. Estradiol: mediator of memories, spine density and cognitive resilience to stress in female rodents. J Steroid Biochem Mol Biol. 2016;2016(160):189–95.
Rossetti MF, Cambiasso MJ, Holschbach MA, et al. Oestrogens and progestagens: synthesis and action in the brain. J Neuroendocrinol. 2016. https://doi.org/10.1111/jne.12402.
Engler-Chiurazzi EB, Singh M, Simpkins JW. From the 90′s to now: a brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res. 2016;1633:96–100.
Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284–90.
Goodman Y, Bruce AJ, Cheng B, et al. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem. 1996;66(5):1836–44.
Foy MR, Akopian G, Thompson RF. Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus. Learn Mem. 2008;15(11):820–2.
Prakapenka AV, Hiroi R, Quihuis AM, et al. Contrasting effects of individual versus combined estrogen and progestogen regimens as working memory load increases in middle-aged ovariectomized rats: one plus one does not equal two. Neurobiol Aging. 2018;2018(64):1–14.
Koebele SV, Bimonte-Nelson HA. The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory. Exp Gerontol. 2017;2017(94):14–23.
Taylor GT, Manzella FM, Huffman J, et al. Cognition in female rats after blocking conversion of androgens to estrogens. Horm Behav. 2017;2017(90):84–9.
Hara Y, Park CS, Janssen WG, et al. Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys. Neurobiol Aging. 2012;33(2):421.e17–28.
Kurita K, Henderson VW, Gatz M, et al. Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women. Fertil Steril. 2016;106(3):749–56.
Amtul Z, Wang L, Westaway D, et al. Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer’s disease. Neuroscience. 2010;169(2):781–6.
Coker LH, Espeland MA, Rapp SR, et al. Postmenopausal hormone therapy and cognitive outcomes: the Women’s Health Initiative Memory Study (WHIMS). J Steroid Biochem Mol Biol. 2010;118(4–5):304–10.
Resnick SM, Coker LH, Maki PM, et al. The Women’s Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline. Clin Tr. 2004;1:440–50.
Anderson GL, Manson J, Wallace R, et al. Implementation of the Women’s Health Initiative study design. Ann Epidemiol. 2003;13:S5–17.
Speth RC, D’Ambra M, Ji H, et al. A heartfelt message, estrogen replacement therapy: use it or lose it. Am J Physiol Heart Circ Physiol. 2018. https://doi.org/10.1152/ajpheart.00041.2018.
Lobo RA. Where are we 10 years after the Women’s health initiative? J Clin Endocrinol Metab. 2013;98(5):1771–80.
Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology. 2017;88(11):1062–8.
Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Women’s Health Initiative 10 years on. Climacteric. 2012;15(3):256–62.
Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI study. Neurology. 2009;72(2):135–42.
Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer’s disease. Curr Opin Psychiatry. 2018;31(2):133–9.
Maki PM. Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause. 2013;20(6):695–709.
Tschanz JT, Norton MC, Zandi PP, et al. The cache county study on memory in aging: factors affecting risk of Alzheimer’s disease and its progression after onset. Int Rev Psychiatry. 2013;25(6):673–85.
Imtiaz B, TolppanenAM SA, Soininen H, et al. Estradiol and cognition in the cardiovascular risk factors, aging and dementia (CAIDE) cohort study. J Alzheimers Dis. 2017;56(2):453–8.
Marder K, Tang MX, Alfaro B, et al. Postmenopausal estrogen use and Parkinson’s disease with and without dementia. Neurology. 1998;50(4):1141–3.
Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: a 2014 update. Mol Cell Endocrinol. 2014;389(1–2):7–12.
Rocca WA, Bower JH, Maraganore DM, et al. Melton LJ 3rd Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69(11):1074–83.
Phung TK, Waltoft BL, Laursen TM, et al. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord. 2010;30(1):43–50.
Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014;82(3):222–9.
Espeland MA, Rapp SR, Manson JE, et al. WHIMSY and WHIMS-ECHO study groups long-term effects on cognitive trajectories of postmenopausal hormone therapy in two age groups. J Gerontol A Biol Sci Med Sci. 2017;72(6):838–45.
Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-cognitive and affective study. PLoS Med. 2015;12(6):e1001833.
Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis. Neurology. 2016;87(7):699–708.
Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol. 2014;2014(6):37–48.
Whitmer RA, Quesenberry CP, Zhou J, et al. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. 2011;69(1):163–9.
Cobin RH, Goodman NF. AACE reproductive endocrinology scientific committee. American association of clinical endocrinologists and American college of endocrinology position statement on menopause-2017 update. Endocr Pract. 2017;23(7):869–80.
Maki PM. Minireview: effects of different HT formulations on cognition. Endocrinology. 2012;153(8):3564–70.
Davis SR, Wahlin-Jacobsen S. Testosterone in women–the clinical significance. Lancet Diabetes Endocrinol. 2015;3(12):980–92.
Henderson VW, Ala T, Sainani KL, et al. Raloxifene for women with Alzheimer disease: a randomized controlled pilot trial. Neurology. 2015;85(22):1937–44.
Yang ZD, Yu J, Zhang Q. Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials. Maturitas. 2013;75(4):341–8.
The NAMS. Hormone therapy position statement advisory panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728–53.
Pines A. Alzheimer’s disease, menopause and the impact of the estrogenic environment. Climacteric. 2016;19(5):430–2.
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Dr Satish V. Khadilkar is presently the Dean and Professor and Head at the Department Neurology at the Bombay Hospital Institute of Medical Sciences, Mumbai. Dr Varsha A. Patil is Clinical Associate, Neurology at Department Neurology at the Bombay Hospital Institute of Medical Sciences, Mumbai.
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Khadilkar, S.V., Patil, V.A. Sex Hormones and Cognition: Where Do We Stand?. J Obstet Gynecol India 69, 303–312 (2019). https://doi.org/10.1007/s13224-019-01223-5
- Alzheimer’s disease
- Hormone therapy
- Menopausal hormonal therapy
- Sex hormones