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REVIEW ARTICLE
Factors contributing to the development of cognitive function disorders in postmenopausal women
 
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Department and Clinic of Gynaecological Endocrinology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Poland
 
 
Submission date: 2025-02-17
 
 
Final revision date: 2025-10-06
 
 
Acceptance date: 2025-10-10
 
 
Online publication date: 2026-09-18
 
 
Corresponding author
Agata Ewa Gondek   

Department and Clinic of Gynecological Endocrinology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice
 
 
 
KEYWORDS
TOPICS
ABSTRACT
Menopause is the last menstrual bleeding, after which no further menstruation occurs for 12 months. Typically, it manifests between the ages of 45 and 55 years. The endocrine activity of the ovaries stops, resulting in a decrease in hormone production. Oestrogen deficiency during the postmenopausal period may increase the risk of neurodegeneration. Changes in the signalling of oestrogen receptors  and  (ER and ER), as well as polymorphisms Pvu II and Xba I in the ER receptor, may influence susceptibility to Alzheimer’s disease. Oestrogens protect neurons from damage caused by amyloid . Oestrogens also play a role in the mitochondrial bioenergetics of neurons and in preventing brain inflammation associated with neurodegenerative diseases. The potential role of menopausal hormone therapy in reducing dementia risk is currently under investigation. Despite the neurobiological rationale for oestrogen’s protective effects on Alzheimer’s risk and promising animal model evidence, results from observational, clinical, and prospective studies remain inconclusive.
REFERENCES (46)
1.
Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L. Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther. 2024; 9: 211.
 
2.
Jessen F, Amariglio RE, Buckley RF, van der Flier WM, Han Y, Molinuevo JL, Rabin L, Rentz DM, Rodriguez-Gomez O, Saykin AJ, Sikkes SAM, Smart CM, Wolfsgruber S, Wagner M. The characterisation of subjective cognitive decline. Lancet Neurol. 2020; 19: 271-278.
 
3.
Peng L, Bestard-Lorigados I, Song W. The synapse as a treatment avenue for Alzheimer’s Disease. Mol Psychiatry. 2022; 27: 2940-2949.
 
4.
Reddy AP, Reddy PH. Mitochondria-targeted molecules as potential drugs to treat patients with Alzheimer’s disease. Progress Mol Biol Transl Sci. 2017; 146: 173-201.
 
5.
Depypere H, Vergallo A, Lemercier P, Lista S, Benedet A, Ashton N, Cavedo E, Zetterberg H, Blennow K, Vanmechelen E, Hampel H; Neurodegeneration Precision Medicine Initiative (NPMI). Menopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer’s disease. Alzheimers Dement. 2023; 19: 1320-1330.
 
6.
Talaulikar V. Menopause transition: physiology and symptoms. Best Pract Res Clin Obstet Gynaecol. 2022; 81: 3-7.
 
7.
Al-Azzawi F, Palacios S. Hormonal changes during menopause. Maturitas. 2009; 63(2): 135-137.
 
8.
Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019; 116: 135-170.
 
9.
Davis SR, Pinkerton J, Santoro N, Simoncini T. Menopause – biology, consequences, supportive care, and therapeutic options. Cell. 2023; 186(19): 4038-4058.
 
10.
Hojo Y, Murakami G, Mukai H, Higo S, Hatanaka Y, Ogiue- Ikeda M, Ishii H, Kimoto T, Kawato S. Estrogen synthesis in the brain – role in synaptic plasticity and memory. Mol Cell Endocrinol. 2008; 290(1-2): 31-43.
 
11.
Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013; 19(3): 197-209.
 
12.
Warfvinge K, Krause DN, Maddahi A, Edvinsson JCA, Edvinsson L, Haanes KA. Estrogen receptors ,  and GPER in the CNS and trigeminal system – molecular and functional aspects. J Headache Pain. 2020; 21(1): 131.
 
13.
Devidze N, Fujimori K, Urade Y, Pfaff DW, Mong JA. Estradiol regulation of lipocalin-type prostaglandin D synthase promoter activity: evidence for direct and indirect mechanisms. Neuroscience Lett. 2010; 474(1): 17-21.
 
14.
Chen P, Li B, Ou‑Yang L. Role of estrogen receptors in health and disease. Front Endocrinol. 2022; 13: 839005.
 
15.
Corbo RM, Gambina G, Ruggeri M, Scacchi R. Association of estrogen receptor  (ESR1) Pvu II and Xba I polymorphisms with sporadic Alzheimer’s disease and their effect on apolipoprotein E concentrations. Dementia Geriatr Cogn Disord. 2006; 22(1): 67-72.
 
16.
Toran-Allerand CD, Miranda RC, Bentham WD, Sohrabji F, Brown TJ, Hochberg RB, MacLusky NJ. Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci. 1992; 89(10): 4668-4672.
 
17.
Ali N, Sohail R, Jaffer SR, Siddique S, Kaya B, Atowoju I, Imran A, Wright W, Pamulapati S, Choudhry F, Akbar A, Khawaja UA. The role of estrogen therapy as a protective factor for Alzheimer’s disease and dementia in postmenopausal women: a comprehensive review of the literature. Cureus. 2023; 15(8): e43053.
 
18.
Behl C, Skutella T, Frank LH, Post A, Widmann M, Newton CJ, Holsboer F. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol. 1997; 51(4): 535-541.
 
19.
Bagit A, Hayward GC, MacPherson REK. Exercise and estrogen: common pathways in Alzheimer’s disease pathology. Am J Physiol Endocrinol Metab. 2021; 321(1): E164-E168.
 
20.
Thomas T, Rhodin JA. Vascular actions of estrogen and Alzheimer’s disease. Ann N Y Acad Sci. 2000; 903: 501-509.
 
21.
Xiang D, Liu Y, Zhou S, Zhou E, Wang Y. Protective effects of estrogen on cardiovascular disease mediated by oxidative stress. Oxid Med Cell Longev. 2021; 2021: 5523516.
 
22.
Villaseca P, Cisternas P, Inestrosa NC. Menopause and development of Alzheimer’s disease: roles of neural glucose metabolism and Wnt signaling. Front Endocrinol. 2022; 13: 1021796.
 
23.
Triaca V, Sposato V, Bolasco G, Ciotti MT, Pelicci P, Bru- ni AC, Cupidi C, Maletta R, Feligioni M, Nisticò R, Canu N, Calissano P. NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer’s disease. Aging Cell. 2016; 15(4): 661-672.
 
24.
Chang WC, Wang JH, Ding DC. Conjugated equine estrogen used in postmenopausal women associated with a higher risk of stroke than estradiol. Sci Rep. 2021; 11: 10801.
 
25.
Valencia-Olvera AC, Maldonado Weng J, Christensen A, LaDu MJ, Pike CJ. Role of estrogen in women’s Alzhei- mer’s disease risk as modified by APOE. J Neuroendocrinol. 2022; 34(12): e13209.
 
26.
Yaffe K, Haan M, Byers A, Tangen C, Kuller LM. Estrogen use, APOE, and cognitive decline: evidence of gene–environment interaction. Neurology. 2000; 54(10): 1949-1954.
 
27.
Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J Neurosci Res. 2017; 95(10): 2025-2029.
 
28.
Maitra R, Malik P, Mukherjee TK. Targeting estrogens and various estrogen-related receptors against non-small cell lung cancers: a perspective. Cancers. 2022; 14(1): 80.
 
29.
Tian X, Lou S, Shi R. From mitochondria to sarcopenia: role of 17 estradiol and testosterone. Front Endocrinol. 2023; 14: 1156583.
 
30.
Mishra P, Chan DC. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol. 2014; 15(10): 634-646.
 
31.
Gleason CE, Dowling NM, Wharton W, Manson JE, Mil- ler VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G. 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.
 
32.
Espeland MA, Shumaker SA, Leng I, Manson JE, Brown CM, LeBlanc ES, Vaughan L, Robinson J, Rapp SR, Goveas JS, Lane D. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med. 2013; 173(15): 1429-1436.
 
33.
Henderson VW, St. John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis. Neurology. 2016; 87(7): 699-708.
 
34.
Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002; 288(17): 2170-2172.
 
35.
Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008; 31(10): 529-537.
 
36.
Kim YJ, Soto M, Branigan GL, Rodgers K, Brinton RD. Association between menopausal hormone therapy and risk of neurodegenerative diseases: implications for precision hormone therapy. Alzheimer’s Dement. 2021; 7(1): e12174.
 
37.
Coughlan GT, Betthauser TJ, Boyle R, Koscik RL, Klin- ger HM, Chibnik LB, Jonaitis EM, Yau WYW, Wenzel A, Christian BT, Gleason CE, Saelzler UG, Properzi MJ, Schultz AP, Hanseeuw BJ, Manson JAE, Rentz DM, Johnson KA, Sperling R, Johnson SC, Buckley RF. Association of age at menopause and hormone therapy use with tau and -amyloid positron emission tomography. JAMA Neurol. 2023; 80(5): 462-473.
 
38.
Kim H, Yoo J, Han K, Lee GY, Fava M, Mischoulon D, Jeon HJ. Hormone therapy and the decreased risk of dementia in women with depression: a population-based cohort study. Alzheimers Res Ther. 2022; 14: 83.
 
39.
Swerdloff RS, Wang C, Ensrud KE. Safety of testosterone-replacement therapy in older men. N Engl J Med. 2023; 389(2): 149-157.
 
40.
Patel R, Thomas S, Kaur G. Mechanisms of testosterone’s neuroprotective action in the aging brain. Front Neurosci. 2021; 15: 641537.
 
41.
Marriott RJ, Murray K, Flicker L, Hankey GJ, Matsumo- to AM, Dwivedi G, Antonio L, Almeida OP, Bhasin S, Dobs AS, Handelsman DJ, Haring R, O’Neill TW, Ohls- son C, Orwoll ES, Vanderschueren D, Wittert GA, Wu FCW, Yeap BB. Lower serum testosterone concentrations are associated with a higher incidence of dementia in men: The UK Biobank prospective cohort study. Alzheimers Dement. 2022; 18(3): 1907-1918.
 
42.
Banica T, Verroken C, Reyns T, Mahmoud A, T’Sjoen G, Fiers T, Kaufman JM, Lapauw B. Early decline of androgen levels in healthy adult men: an effect of aging per se? A prospective cohort study. J Clin Endocrinol Metab. 2021; 106(4): 1074-1083.
 
43.
Whittaker J, Wu K. Low-fat diets and testosterone in men: systematic review and meta-analysis of intervention studies. J Steroid Biochem Mol Biol. 2021; 210: 105878.
 
44.
Šturm T, Kocijančič J, Milanič M. et al. Effects of chronic alcohol consumption on the hypothalamic–pituitary– gonadal axis in men: a systematic review and meta- analysis. Alcohol Clin Exp Res. 2023; 47(3): 456-467.
 
45.
Xu W, Tan L, Wang HF, et al. The impact of comorbidities on cognitive decline: a meta-analysis. Alzheimers Dement. 2022; 18(1): 133-143.
 
46.
Chen J, Huang X, Li Z, et al. Effects of testosterone supplementation on cognitive function in hypogonadal men: a systematic review and meta-analysis. Neurology. 2022; 98(12): e1234-e1242.
 
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