{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T23:15:26Z","timestamp":1790118926223,"version":"4.0.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,7]],"date-time":"2017-04-07T00:00:00Z","timestamp":1491523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,7]],"date-time":"2017-04-07T00:00:00Z","timestamp":1491523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Estrogens play a physiologically important role in the brain, but controversies exist regarding the association between Alzheimer\u2019s disease (AD) and estrogens. Estrogen-related factors were comprehensively examined in frontal lobe tissues from autopsied AD patients, and compared with controls. Concentrations of estrogens, expression of estrogen receptors (ERs), and estrogen-metabolizing enzymes (EMEs) which are important for determining the peripheral estrogen concentrations, were examined using liquid chromatography tandem mass spectrometry, immunohistochemistry, and quantitative real-time PCR, respectively. Body mass index (BMI), known to correlate with the serum estrogen concentrations, was also taken into consideration. There were no significant differences in estrogen concentrations or each EME level between the two groups in both the cortex and white matter, whereas glial nuclear ER-\u03b2 expression was significantly lower in white matter from the AD group than the control group (Allred score, 3.2\u2009\u00b1\u20090.3 and 6.5\u2009\u00b1\u20090.3, respectively.\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Estrogen concentrations were found to closely correlate with BMI, particularly in controls. ER-\u03b2 loss in the white matter from the AD group suggests the necessity of studying the effects of estrogens on glias as well as neurons in the etiology of AD. The correlation between BMI and estrogen concentrations in the frontal lobe suggests the importance of non-brain sources of estrogens.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-00815-3","type":"journal-article","created":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T10:03:52Z","timestamp":1491213832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Estrogen-Related Factors in the Frontal Lobe of Alzheimer\u2019s Disease Patients and Importance of Body Mass Index"],"prefix":"10.1038","volume":"7","author":[{"given":"Naoko","family":"Honma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigehira","family":"Saji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetuo","family":"Mikami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seijiro","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Murayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,7]]},"reference":[{"key":"815_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/nrn3856","volume":"16","author":"MA Arevalo","year":"2015","unstructured":"Arevalo, M. A., Azcoitia, I. & Garcia-Segura, L. The neuroprotective actions of oestradiol and oestrogen receptors. Nat. Rev. Neurosci. \n                           16, 17\u201329 (2015).","journal-title":"Nat. Rev. Neurosci."},{"key":"815_CR2","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1111\/j.1365-2826.2009.01857.x","volume":"21","author":"N Harada","year":"2009","unstructured":"Harada, N., Wakatsuki, T., Aste, N., Yoshimura, N. & Honda, S. I. Functional analysis of neurosteroidal oestrogen using gene-disrupted and transgenic mice. J. Neuroendocrinol \n                           21, 365\u2013369 (2009).","journal-title":"J. Neuroendocrinol"},{"key":"815_CR3","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.yfrne.2013.08.001","volume":"35","author":"JR Rettberg","year":"2014","unstructured":"Rettberg, J. R., Yao, J. & Brinton, R. D. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front. Neuroendocrinol. \n                           35, 8\u201330 (2014).","journal-title":"Front. Neuroendocrinol."},{"key":"815_CR4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3233\/JAD-142730","volume":"45","author":"P Agostinho","year":"2015","unstructured":"Agostinho, P., Pli\u00e1ssova, A., Oliveira, C. R. & Cunha, R. A. Localization and Trafficking of Amyloid-\u03b2 Protein Precursor and Secretases: Impact on Alzheimer\u2019s Disease. J. Alzheimer\u2019s Dis. \n                           45, 329\u2013347 (2015).","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"815_CR5","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.2165\/00003495-200666160-00004","volume":"66","author":"M H\u00fcll","year":"2006","unstructured":"H\u00fcll, M., Berger, M. & Heneka, M. Disease-modifying therapies in Alzheimer\u2019s disease: how far have we come? Drugs \n                           66, 2075\u20132093 (2006).","journal-title":"Drugs"},{"key":"815_CR6","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1007\/s12035-012-8377-3","volume":"47","author":"R Li","year":"2013","unstructured":"Li, R. et al. Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer\u2019s transgenic mice. Mol. Neurobiol. \n                           47, 857\u2013867 (2013).","journal-title":"Mol. Neurobiol."},{"key":"815_CR7","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/nrd3551","volume":"10","author":"S Nilsson","year":"2011","unstructured":"Nilsson, S., Koehler, K. F. & Gustafsson, J. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev Drug Discov \n                           10, 778\u2013792 (2011).","journal-title":"Nat Rev Drug Discov"},{"key":"815_CR8","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.arr.2015.08.001","volume":"24","author":"L Zhao","year":"2015","unstructured":"Zhao, L., Woody, S. K. & Chhibber, A. Estrogen receptor beta in Alzheimer\u2019s disease: From mechanisms to therapeutics. Ageing Res. Rev. \n                           24, 178\u2013190 (2015).","journal-title":"Ageing Res. Rev."},{"key":"815_CR9","doi-asserted-by":"publisher","first-page":"3555","DOI":"10.1210\/jcem.86.8.7736","volume":"86","author":"S Khosla","year":"2001","unstructured":"Khosla, S., Melton, L. J., Atkinson, E. J. & O\u2019Fallon, W. M. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J. Clin. Endocrinol. Metab. \n                           86, 3555\u20133561 (2001).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"815_CR10","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/S0140-6736(96)03356-9","volume":"348","author":"MX Tang","year":"1996","unstructured":"Tang, M. X. et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer\u2019s disease. Lancet \n                           348, 429\u2013432 (1996).","journal-title":"Lancet"},{"key":"815_CR11","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1001\/jama.289.20.2651","volume":"289","author":"SA Shumaker","year":"2003","unstructured":"Shumaker, S. A. et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women\u2019s Health Initiative Memory Study: a randomized controlled trial. JAMA \n                           289, 2651\u20132662 (2003).","journal-title":"JAMA"},{"key":"815_CR12","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1111\/pin.12326","volume":"65","author":"N Honma","year":"2015","unstructured":"Honma, N., Hosoi, T., Arai, T. & Takubo, K. Estrogen and cancers of the colorectum, breast, and lung in postmenopausal women. Pathol. Int. \n                           65, 451\u2013459 (2015).","journal-title":"Pathol. Int."},{"key":"815_CR13","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.exger.2006.06.032","volume":"42","author":"KM Dhandapani","year":"2007","unstructured":"Dhandapani, K. M. & Brann, D. W. Role of astrocytes in estrogen-mediated neuroprotection. Exp. Gerontol. \n                           42, 70\u201375 (2007).","journal-title":"Exp. Gerontol."},{"key":"815_CR14","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.exger.2006.05.013","volume":"42","author":"RG Struble","year":"2007","unstructured":"Struble, R. G., Nathan, B. P., Cady, C., Cheng, X. & McAsey, M. Estradiol regulation of astroglia and apolipoprotein E: an important role in neuronal regeneration. Exp. Gerontol. \n                           42, 54\u201363 (2007).","journal-title":"Exp. Gerontol."},{"key":"815_CR15","doi-asserted-by":"publisher","first-page":"2502","DOI":"10.1158\/1055-9965.EPI-06-0499","volume":"15","author":"S Mahabir","year":"2006","unstructured":"Mahabir, S. et al. Usefulness of body mass index as a sufficient adiposity measurement for sex hormone concentration associations in postmenopausal women. Cancer Epidemiol. Biomarkers Prev. \n                           15, 2502\u20132507 (2006).","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"815_CR16","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1200\/JCO.2009.25.6529","volume":"28","author":"ME Hammond","year":"2010","unstructured":"Hammond, M. E. et al. American Society of Clinical Oncology\/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J. Clin. Oncol. \n                           28, 2784\u20132795 (2010).","journal-title":"J. Clin. Oncol."},{"key":"815_CR17","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1200\/JCO.1999.17.5.1474","volume":"17","author":"JM Harvey","year":"1999","unstructured":"Harvey, J. M., Clark, G. M., Osborne, C. K. & Allred, D. C. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J. Clin. Oncol. \n                           17, 1474\u20131481 (1999).","journal-title":"J. Clin. Oncol."},{"key":"815_CR18","doi-asserted-by":"publisher","first-page":"3727","DOI":"10.1200\/JCO.2007.14.2968","volume":"26","author":"N Honma","year":"2008","unstructured":"Honma, N. et al. Clinical importance of estrogen receptor-beta evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J. Clin. Oncol. \n                           26, 3727\u20133734 (2008).","journal-title":"J. Clin. Oncol."},{"key":"815_CR19","doi-asserted-by":"publisher","first-page":"19198","DOI":"10.1073\/pnas.0505203102","volume":"102","author":"X Yue","year":"2005","unstructured":"Yue, X. et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer\u2019s disease animal model. Proc. Natl. Acad. Sci. USA \n                           102, 19198\u201319203 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"815_CR20","doi-asserted-by":"publisher","first-page":"21467","DOI":"10.1038\/srep21467","volume":"6","author":"Y Ma","year":"2016","unstructured":"Ma, Y. et al. Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor beta. Sci. Rep. \n                           6, 21467 (2016).","journal-title":"Sci. Rep."},{"key":"815_CR21","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1016\/j.neurobiolaging.2009.12.010","volume":"32","author":"L Zhao","year":"2011","unstructured":"Zhao, L. et al. 17beta-Estradiol regulates insulin-degrading enzyme expression via an ERbeta\/PI3-K pathway in hippocampus: relevance to Alzheimer\u2019s prevention. Neurobiol. Aging \n                           32, 1949\u20131963 (2011).","journal-title":"Neurobiol. Aging"},{"key":"815_CR22","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1210\/jc.2003-030862","volume":"89","author":"A Hestiantoro","year":"2004","unstructured":"Hestiantoro, A. & Swaab, D. F. Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer\u2019s disease neuropathology. J. Clin. Endocrinol. Metab. \n                           89, 1912\u20131925 (2004).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"815_CR23","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.neulet.2004.01.075","volume":"360","author":"B Hong-Goka","year":"2004","unstructured":"Hong-Goka, B. & Chang, F. L. Estrogen receptors alpha and beta in choroid plexus epithelial cells in Alzheimer\u2019s disease. Neurosci. Lett. \n                           360, 113\u2013116 (2004).","journal-title":"Neurosci. Lett."},{"key":"815_CR24","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.humpath.2003.11.004","volume":"35","author":"YP Lu","year":"2004","unstructured":"Lu, Y. P., Zeng, M., Swaab, D. F., Ravid, R. & Zhou, J. N. Colocalization and alteration of estrogen receptor-alpha and -beta in the hippocampus in Alzheimer\u2019s disease. Hum. Pathol. \n                           35, 275\u2013280 (2004).","journal-title":"Hum. Pathol."},{"key":"815_CR25","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0006-8993(01)02610-5","volume":"908","author":"E Savaskan","year":"2001","unstructured":"Savaskan, E., Olivieri, G., Meier, F., Ravid, R. & M\u00fcller-Spahn, F. Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer\u2019s disease. Brain Res. \n                           908, 113\u2013119 (2001).","journal-title":"Brain Res."},{"key":"815_CR26","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S0197-4580(00)00255-4","volume":"22","author":"TA Ishunina","year":"2001","unstructured":"Ishunina, T. A. & Swaab, D. F. Increased expression of estrogen receptor alpha and beta in the nucleus basalis of Meynert in Alzheimer\u2019s disease. Neurobiol. Aging \n                           22, 417\u2013426 (2001).","journal-title":"Neurobiol. Aging"},{"key":"815_CR27","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/S0006-8993(03)03347-X","volume":"988","author":"TA Ishunina","year":"2003","unstructured":"Ishunina, T. A., van Heerikhuize, J. J., Ravid, R. & Swaab, D. F. Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer\u2019s disease. Brain Res. \n                           988, 84\u201396 (2003).","journal-title":"Brain Res."},{"key":"815_CR28","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1212\/01.wnl.0000176061.33817.90","volume":"65","author":"AS Buchman","year":"2005","unstructured":"Buchman, A. S. et al. Change in body mass index and risk of incident Alzheimer disease. Neurology \n                           65, 892\u2013897 (2005).","journal-title":"Neurology"},{"key":"815_CR29","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/S2213-8587(15)00033-9","volume":"3","author":"N Qizilbash","year":"2015","unstructured":"Qizilbash, N. et al. BMI and risk of dementia in two million people over two decades: a retrospective cohort study. Lancet Diabetes Endocrinol \n                           3, 431\u2013436 (2015).","journal-title":"Lancet Diabetes Endocrinol"},{"key":"815_CR30","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1212\/01.wnl.0000247046.90574.0f","volume":"67","author":"AS Buchman","year":"2006","unstructured":"Buchman, A. S., Schneider, J. A., Wilson, R. S., Bienias, J. L. & Bennett, D. A. Body mass index in older persons is associated with Alzheimer disease pathology. Neurology \n                           67, 1949\u20131954 (2006).","journal-title":"Neurology"},{"key":"815_CR31","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1111\/j.1349-7006.2011.02018.x","volume":"102","author":"N Honma","year":"2011","unstructured":"Honma, N. et al. Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3\u03b2, 17\u03b2-diol. Cancer Sci \n                           102, 1848\u20131854 (2011).","journal-title":"Cancer Sci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00815-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00815-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00815-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T22:35:47Z","timestamp":1671748547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00815-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,7]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["815"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-00815-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,7]]},"assertion":[{"value":"2 September 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"726"}}