Sex Hormones and Cognition: Where Do We Stand?

  • Satish V. KhadilkarEmail author
  • Varsha A. Patil
Review Article


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.


Alzheimer’s disease Cognition Dementia Estrogen Estradiol Hormone therapy Menopausal hormonal therapy Memory Sex hormones 


Author’s Contribution

SVK and VAP were involved in literature research, manuscript preparation, manuscript editing and revision. Both the authors have read the manuscript and approved the final version.

Compliance with Ethical Standards

Conflict of interest

Both the authors declare that they do not have any conflict of interest.

Human and Animal Rights

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    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.Google Scholar
  2. 2.
    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.Google Scholar
  3. 3.
    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.Google Scholar
  4. 4.
    Alzheimer’s NM. Disease: prototype of cognitive deterioration, valuable lessons to understand human cognition. Neurol Clin. 2016;34(1):69–131.Google Scholar
  5. 5.
    American Psychiatric Association. DSM-5: diagnostic and statistical manual of mental disorders, vol. 5. Washington, DC: American Psychiatric Association; 2013.Google Scholar
  6. 6.
    Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci. 2016;18(4):437–46.Google Scholar
  7. 7.
    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.Google Scholar
  8. 8.
    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.Google Scholar
  9. 9.
    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.Google Scholar
  10. 10.
    Gliebus GP. Memory dysfunction continuum (MinneapMinn). Behav Neurol Psychiatry. 2018;24(3):727–44.Google Scholar
  11. 11.
    Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7(3):137–52.Google Scholar
  12. 12.
    Bhattacharyya KB. James wenceslaus papez, his circuit, and emotion. Ann Indian Acad Neurol. 2017;20(3):207–10.Google Scholar
  13. 13.
    Hamson DK, Roes MM, Galea LA. Sex hormones and cognition: neuroendocrine influences on memory and learning. Compr Physiol. 2016;6(3):1295–337.Google Scholar
  14. 14.
    Palm R, Ayala-Fontanez N, Garcia Y, et al. Neuroendocrinology-based therapy for Alzheimer’s disease. BioFactors. 2012;38(2):123–32.Google Scholar
  15. 15.
    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.Google Scholar
  16. 16.
    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.Google Scholar
  17. 17.
    Vogel JJ, Bowers CA, Vogel DS. Cerebral lateralization of spatial abilities: a meta-analysis. Brain Cogn. 2003;52(2):197–204.Google Scholar
  18. 18.
    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.Google Scholar
  19. 19.
    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.Google Scholar
  20. 20.
    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.Google Scholar
  21. 21.
    Mitchell ES, Woods NF. Cognitive symptoms during the menopausal transition and early postmenopause. Climacteric. 2011;14(2):252–61.Google Scholar
  22. 22.
    Weber MT, Rubin LH, Maki PM. Cognition in perimenopause: the effect of transition stage. Menopause. 2013;20(5):511–7.Google Scholar
  23. 23.
    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.Google Scholar
  24. 24.
    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.Google Scholar
  25. 25.
    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.Google Scholar
  26. 26.
    Luine VN. Estradiol and cognitive function: past, present and future. Horm Behav. 2014;66(4):602–18.Google Scholar
  27. 27.
    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.Google Scholar
  28. 28.
    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.Google Scholar
  29. 29.
    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.Google Scholar
  30. 30.
    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.Google Scholar
  31. 31.
    Rossetti MF, Cambiasso MJ, Holschbach MA, et al. Oestrogens and progestagens: synthesis and action in the brain. J Neuroendocrinol. 2016. Scholar
  32. 32.
    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.Google Scholar
  33. 33.
    Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284–90.Google Scholar
  34. 34.
    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.Google Scholar
  35. 35.
    Foy MR, Akopian G, Thompson RF. Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus. Learn Mem. 2008;15(11):820–2.Google Scholar
  36. 36.
    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.Google Scholar
  37. 37.
    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.Google Scholar
  38. 38.
    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.Google Scholar
  39. 39.
    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.Google Scholar
  40. 40.
    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.Google Scholar
  41. 41.
    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.Google Scholar
  42. 42.
    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.Google Scholar
  43. 43.
    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.Google Scholar
  44. 44.
    Anderson GL, Manson J, Wallace R, et al. Implementation of the Women’s Health Initiative study design. Ann Epidemiol. 2003;13:S5–17.Google Scholar
  45. 45.
    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. Scholar
  46. 46.
    Lobo RA. Where are we 10 years after the Women’s health initiative? J Clin Endocrinol Metab. 2013;98(5):1771–80.Google Scholar
  47. 47.
    Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology. 2017;88(11):1062–8.Google Scholar
  48. 48.
    Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Women’s Health Initiative 10 years on. Climacteric. 2012;15(3):256–62.Google Scholar
  49. 49.
    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.Google Scholar
  50. 50.
    Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer’s disease. Curr Opin Psychiatry. 2018;31(2):133–9.Google Scholar
  51. 51.
    Maki PM. Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause. 2013;20(6):695–709.Google Scholar
  52. 52.
    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.Google Scholar
  53. 53.
    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.Google Scholar
  54. 54.
    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.Google Scholar
  55. 55.
    Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: a 2014 update. Mol Cell Endocrinol. 2014;389(1–2):7–12.Google Scholar
  56. 56.
    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.Google Scholar
  57. 57.
    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.Google Scholar
  58. 58.
    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.Google Scholar
  59. 59.
    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.Google Scholar
  60. 60.
    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.Google Scholar
  61. 61.
    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.Google Scholar
  62. 62.
    Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol. 2014;2014(6):37–48.Google Scholar
  63. 63.
    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.Google Scholar
  64. 64.
    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.Google Scholar
  65. 65.
    Maki PM. Minireview: effects of different HT formulations on cognition. Endocrinology. 2012;153(8):3564–70.Google Scholar
  66. 66.
    Davis SR, Wahlin-Jacobsen S. Testosterone in women–the clinical significance. Lancet Diabetes Endocrinol. 2015;3(12):980–92.Google Scholar
  67. 67.
    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.Google Scholar
  68. 68.
    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.Google Scholar
  69. 69.
    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.Google Scholar
  70. 70.
    Pines A. Alzheimer’s disease, menopause and the impact of the estrogenic environment. Climacteric. 2016;19(5):430–2.Google Scholar

Copyright information

© Federation of Obstetric & Gynecological Societies of India 2019

Authors and Affiliations

  1. 1.Department of NeurologyBombay Hospital Institute of Medical SciencesMumbaiIndia

Personalised recommendations