Estrogen: a Master Regulator of Bioenergetic Systems in the Brain and Body

Overview

Journal Front Neuroendocrinol

Specialty Endocrinology

Date 2013 Sep 3

PMID 23994581

Citations 215

Authors

Jamaica R Rettberg

Jia Yao

Roberta Diaz Brinton

Affiliations

Soon will be listed here.

Abstract

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.

Citing Articles

The interplay between age at menopause and synaptic integrity on Alzheimer's disease risk in women.

Wood Alexander M, Honer W, Saloner R, Galea L, Bennett D, Rabin J Sci Adv. 2025; 11(10):eadt0757.

PMID: 40043118 PMC: 11881898. DOI: 10.1126/sciadv.adt0757.

Single-Cell Analysis of Sex and Gender Differences in the Human Brain During Development and Disease.

Zelco A, Joshi A Cell Mol Neurobiol. 2025; 45(1):20.

PMID: 40016536 PMC: 11868228. DOI: 10.1007/s10571-025-01536-2.

Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo.

Ghimire N, Welch M, Secunda C, Fink A, Lawan A Cells. 2025; 14(4).

PMID: 39996734 PMC: 11853640. DOI: 10.3390/cells14040261.

Classification and identification of risk factors for type 2 diabetes.

Tang S, Zhao X, An X, Sun W, Kang X, Sun Y World J Diabetes. 2025; 16(2):100371.

PMID: 39959280 PMC: 11718467. DOI: 10.4239/wjd.v16.i2.100371.

Postprandial glycaemic response and pain sensitivity in breast cancer survivors suffering from chronic pain: a double-blind, randomised controlled cross-over pilot experiment.

Yilmaz S, Elma O, Malfliet A, Nijs J, Clarys P, Coppieters I Support Care Cancer. 2025; 33(2):103.

PMID: 39820733 DOI: 10.1007/s00520-024-09117-7.

References

Edland S, Rocca W, Petersen R, Cha R, Kokmen E . Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, Minn. Arch Neurol. 2002; 59(10):1589-93. DOI: 10.1001/archneur.59.10.1589. View

Greco S, Sarkar S, Johnston J, Tezapsidis N . Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun. 2009; 380(1):98-104. PMC: 2657956. DOI: 10.1016/j.bbrc.2009.01.041. View

Jayaraman A, Carroll J, Morgan T, Lin S, Zhao L, Arimoto J . 17β-estradiol and progesterone regulate expression of β-amyloid clearance factors in primary neuron cultures and female rat brain. Endocrinology. 2012; 153(11):5467-79. PMC: 3473201. DOI: 10.1210/en.2012-1464. View

Singh M . Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine. 2001; 14(3):407-15. DOI: 10.1385/ENDO:14:3:407. View

Carlo C, Tommaselli G, Sammartino A, Bifulco G, Nasti A, Nappi C . Serum leptin levels and body composition in postmenopausal women: effects of hormone therapy. Menopause. 2004; 11(4):466-73. DOI: 10.1097/01.gme.0000109313.11228.2b. View

Muller M, Schupf N, Manly J, Mayeux R, Luchsinger J . Sex hormone binding globulin and incident Alzheimer's disease in elderly men and women. Neurobiol Aging. 2008; 31(10):1758-65. PMC: 2891653. DOI: 10.1016/j.neurobiolaging.2008.10.001. View

Greco S, Sarkar S, Johnston J, Zhu X, Su B, Casadesus G . Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun. 2008; 376(3):536-41. PMC: 2577167. DOI: 10.1016/j.bbrc.2008.09.026. View

Paoletti A, Congia S, Lello S, Tedde D, Orru M, Pistis M . Low androgenization index in elderly women and elderly men with Alzheimer's disease. Neurology. 2004; 62(2):301-3. DOI: 10.1212/01.wnl.0000094199.60829.f5. View

Valla J, Schneider L, Niedzielko T, Coon K, Caselli R, Sabbagh M . Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion. 2006; 6(6):323-30. PMC: 1864936. DOI: 10.1016/j.mito.2006.10.004. View

10.

Gibson G, Haroutunian V, Zhang H, PARK L, Shi Q, Lesser M . Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol. 2000; 48(3):297-303. View

11.

Ukkola O, Santaniemi M . Adiponectin: a link between excess adiposity and associated comorbidities?. J Mol Med (Berl). 2002; 80(11):696-702. DOI: 10.1007/s00109-002-0378-7. View

12.

Mendez P, Wandosell F, Garcia-Segura L . Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms. Front Neuroendocrinol. 2006; 27(4):391-403. DOI: 10.1016/j.yfrne.2006.09.001. View

13.

Lieb W, Beiser A, Vasan R, Tan Z, Au R, Harris T . Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA. 2009; 302(23):2565-72. PMC: 2838501. DOI: 10.1001/jama.2009.1836. View

14.

Blass J . The mitochondrial spiral. An adequate cause of dementia in the Alzheimer's syndrome. Ann N Y Acad Sci. 2001; 924:170-83. DOI: 10.1111/j.1749-6632.2000.tb05576.x. View

15.

Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y . Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010; 75(9):764-70. DOI: 10.1212/WNL.0b013e3181eee25f. View

16.

Milner T, Lubbers L, Alves S, McEwen B . Nuclear and extranuclear estrogen binding sites in the rat forebrain and autonomic medullary areas. Endocrinology. 2008; 149(7):3306-12. PMC: 2453087. DOI: 10.1210/en.2008-0307. View

17.

Burns J, Honea R, Vidoni E, Hutfles L, Brooks W, Swerdlow R . Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging. Biochim Biophys Acta. 2011; 1822(3):333-9. PMC: 3264795. DOI: 10.1016/j.bbadis.2011.06.011. View

18.

Wing R, Jeffery R, Burton L, Thorson C, Kuller L, Folsom A . Change in waist-hip ratio with weight loss and its association with change in cardiovascular risk factors. Am J Clin Nutr. 1992; 55(6):1086-92. DOI: 10.1093/ajcn/55.6.1086. View

19.

Chen J, Eshete M, Alworth W, Yager J . Binding of MCF-7 cell mitochondrial proteins and recombinant human estrogen receptors alpha and beta to human mitochondrial DNA estrogen response elements. J Cell Biochem. 2004; 93(2):358-73. DOI: 10.1002/jcb.20178. View

20.

Ishunina T, Fischer D, Swaab D . Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer's disease. Neurobiol Aging. 2006; 28(11):1670-81. DOI: 10.1016/j.neurobiolaging.2006.07.024. View